Local drug delivery

ABSTRACT

An implant having a coating comprising a polymer matrix is swollen in a pharmaceutical solution whereby pharmaceutically active compound is imbibed into the polymer matrix. When the product is implanted, release of the pharmaceutically active compound from the coating takes place. The polymer is preferably formed from ethylenically unsaturated monomers including a zwitterionic monomer, most preferably 2-methacryloyloxyethyl-2′-trimethylammoniumethyl-phosphate inner salt. The monomers from which the polymer is formed may further include surface binding monomers, such as hydrophobic group containing monomers, and crosslinkable monomers, the content of which may be used to control the swellability. Preferably the implant is a stent and the coating of polymer on the exterior wall surface is thicker than the coating of polymer on the interior surface. Release of the drug may be controlled by selection of comonomers. The implant is suitably a stent for use in the cardiovascular system.

This application is a Divisional of U.S. application Ser. No. 09/979,602filed Mar. 15, 2002 (now U.S. Pat. No. 6,872,225); which is a 371 ofPCT/GB00/02087, filed May 30, 2000; the disclosure of each of which isincorporated herein by reference.

The present invention relates to delivery of pharmaceutically activecompounds by an implanted device to a lesion within the body. The deviceis preferably implanted in a body lumen, often effectively permanentlyimplanted. The device is preferably a stent.

A leading cause of mortality within the developed world iscardiovascular disease. Coronary disease is of most concern. Patientshaving such disease usually have narrowing in one or more coronaryarteries. One treatment is coronary stenting, which involves theplacement of a stent at the site of acute artery closure. This type ofsurgery has proved effective in restoring vessel patency and decreasingmyocardial ischemia. However the exposure of currently used metallicstents to flowing blood can result in thrombus formation, smooth musclecell proliferation and acute thrombotic occlusion of the stent.

Non thrombogenic and anti thrombogenic coatings for stents have beendeveloped. One type of balloon expandable stent has been coated withpolymers having pendant zwitterionic groups, specificallyphosphorylcholine (PC) groups, generally described in WO-A-93/01221. Aparticularly successful embodiment of those polymers suitable for use onballoon expandable stents has been described in WO-A-98/30615. Thepolymers coated onto the stent have pendant crosslinkable groups whichare subsequently crosslinked by exposure to suitable conditions,generally heat and/or moisture. Specifically a trialkoxysilylalkyl groupreacts with pendant groups of the same type and/or with hydroxyalkylgroups to generate intermolecular crosslinks. The coatings lead toreduced thrombogenicity.

Fischell, T A in Circulation (1996) 94: 1494-1495 describes testscarried out on various polymer coated stents. A thinner uniformpolyurethane coating, having effectness of 23 μm was observed to have abetter performance than a relatively non uniform thicker layer having athickness in the range 75 to 125 μm. The thicker coatings are furtherdescribed by Vander Giessen, W J et al in Circulation:1996:94:1690-1697.

It has been suggested to utilise coatings on stents as reservoirs forpharmaceutically active agents desired for local delivery. WO-A-95103036describes stents having a coating of an anti-angiogenic compound in apolymeric carrier. Examples of polymers are crosslinked ethylene-vinylacetate copolymers, polycaprolactone and mixtures. In the workedexamples, a stent is coated with a solution containing both polymer andpharmaceutically active compound.

In U.S. Pat. No. 5,380,299 a stent is provided with a coating of athrombolytic compound and optionally an outer layer of an antithrombotic compound. The stent may be precoated with a “primer” such asa cellulose ester or nitrate.

Other drug containing stents and stent coatings are described by Topoland Serruys in Circulation (1998) 98:1802-1820.

McNair et al, in Proceedings of the International Symposium onControlled Release Bioactive Materials (1995) 338-339 describe in vitroinvestigations of release of three model drugs, caffeine, dicloxacillinand vitamin B12, from hydrogel polymers having pendant phosphorylcholinegroups. Alteration of the hydrophilic hydrophobic ratio of the(hydrophilic) phosphorylcholine monomer 2-methacryloyloxyethylphosphorylcholine, (HEMA-PC) and a hydrophobic comonomer andcrosslinking of the polymer allows preparation of polymers having watercontents when swollen in the range 45 to 70 wt %. Crosslinking isachieved by incorporating a reactive monomer3-chloro-2-hydroxypropylmethacrylate. The tests are carried out onmembranes swollen in aqueous drug solutions at 37° C. The release ratesof the model drugs are influenced by the molecular size, solutepartitioning and degree of swelling of the polymer. Dicloxacillin isfound to have a higher half life for release than its molecular sizewould indicate, and the release profile did not appear to be Fickian.

McNair et al, in Medical Device Technology, Dec. 1996, 16-22, describethree series of experiments. In one, polymers formed of HEMA-PC andlauryl methacrylate crosslinked after coating by unspecified means arecocoated with drugs onto stents. Release rates of dexamethazone from thestent, apparently into an aqueous surrounding environment, wasdetermined. Drug release from cast membranes, as model coatings, showedthat the release rate obeyed Fickian diffusion principles, forhydrophilic solutes. In the third series of tests, a non-crosslinkedpolymer coating, free of drug, coated on a stent, had a significantdecrease in platelet adhesion when coated on a stent used in an ex-vivoarteriovenous shunt experiment. The stent coating method was notdescribed in detail.

Stratford et al in “Novel phosphorylcholine based hydrogelpolymers:developments in medical device coatings” describe polymersformed from 2-methacryoyloxyethyl phosphorylcholine, a higher alkylmethacrylate, hydroxypropylmethacrylate and a methacrylate estercomonomer having a reactive pendant group. These PC polymers wereinvestigated to determine the feasibility of delivering drugs and modeldrugs. Results are shown for caffeine, dicloxacillin, vitamin B12,rhodamine and dipyridamole. The device on which the drug is coated is aguide-wire that is, it is not an implant.

In our earlier application, WO-A-0004999, published after the prioritydate of the present application, we describe an apparatus suitable forcoating tubular devices such as stents, which allows control of therelative thicknesses of the coatings on interior and exterior surfacesof the tubular substrate. It is suggested that the interior wall of astent may be provided with a coating having a thickness in the range 5to 200 nm, whilst the exterior surface may have a thicker coating, inthe range 500 to 1500 nm. No specific examples of coating polymers arementioned.

In EP-A-0623354, solutions of drug and polymer in a solvent were used tocoat Wiktor type tantalum wire stents expanded on a 3.5 mm angioplastyballoon. The coating weights per stent were in the range 0.6 to 1.5 mg.Coating was either by dipping the stent in the solution, or by sprayingthe stent from an airbrush. In each case coating involved multiplecoating steps. The drug was for delivery to the vessel wall.

In WO-A-92/11896, a method of delivering drug to the wall of a bloodvessel from a hydrogel polymer on the outside of a balloon catheter isdescribed. The drug is incorporated into the hydrogel which iscompressed against the wall of the lumen upon expansion in the targetvessel. In WO-A-98/11828, a stent is provided with a coating of ahydrogel, which may contain a drug, by transfer from the outer surfaceof the delivery balloon during the delivery procedure. In this case,drug will be delivered from the hydrogel on the interior wall of thestent, into the circulation. Another tubular implant for delivery ofdrug into the circulation, and which is to be implanted in a bloodvessel is described in U.S. Pat. No. 5,735,897. In this device, drug isintended to permeate into the lumen and not through the exterior wall ofthe stent.

In WO-A-9421308, polyurethane coated on a stent is used as a drugdelivery matrix. The stent is precoated with polyurethane which issubsequently immersed in a solution of drug in a solvent which swellsthe polyurethane. The polyurethane coating is at least 20 μm thick, forinstance in the range 25 to 5000 μm. The level of drug in tissueadjacent to the stent as compared to drug in the system following stentdelivery indicated higher levels in adjacent tissues than in thecirculation, for lipophilic drugs, forskolin and etretinate. The methodby which the stent is coated with polyurethane is not described indetail.

In a new process according to the invention, a sterile coated implantcomprising a biostable implant and a coating comprising a polymer matrixis swollen in a pharmaceutical solution comprising a pharmaceuticalactive in solution in a solvent which swells the coating, the swellingbeing carried out at a temperature and for a time to allow swelling toan extent in the range 25 to 95% of the equilibrium swelling at 37° C.in the solution, and

-   -   the coated implant is dried by solvent evaporation to remove 10        to 100% of total solvent, to produce a pharmaceutical active        loaded implant, wherein the polymer of the matrix has pendant        zwitterionic groups.

FIG. 1 represents Fractional Release versus SQRT (square root of time)for Example 3.

FIG. 2 represents Fractional Release versus SQRT for Example 4.

FIG. 3 represents Fractional Release versus SQRT for Example 5.

FIG. 4 represents Amount versus SQRT for Example 6.

FIG. 5 represents Fractional Release versus SQRT for Example 7.

FIG. 6 represents a bar graph illustrating Total Drug Loading versusStent No. (Series 1:1-4, Series 2:5-8, Series 3:9-12, Series 4:13-16)for Example 8.

FIG. 7 represents percentage TTA remaining on Stent versus Time forExample 15.

The polymer coated implant used in the swelling step should be sterile,such as generally provided ready to be used by a surgeon. The swellingstep may be carried out immediately prior to a surgical operation inwhich the product implant is implanted into a patient in whom localrelease of the pharmaceutical active is desired. The sterile implantused in the swelling step may be produced in a preliminary processinvolving a step of coating the biostable implant with a coatingcomposition containing the polymer, or a precursor therefore, curing thecoating to form the polymer matrix and then sterilising the polymercoated implant.

The polymer matrix on the implant must be insoluble in the swellingsolution. Preferably it is also water-insoluble. The polymer isgenerally substantially non-biodegradable (non-resorbable), in anenvironment to which implants are subjected, that is in the body. Thepolymer matrix should, for example, be stable in that environment,should not degrade significantly over a period of at least 2 days,preferably at least 2 weeks for instance a month or more. Although thepolymer may be substantially non-crosslinked, such as formed frommonomers including surface-substantive groups for stable surface bindingon the implant, optimum stability is achieved where the polymer matrixis covalently crosslinked and/or covalently bound to the implantsurface. Preferably the polymer is covalently crosslinked.

A crosslinked polymer matrix coating may be provided on an implant bypolymerisation in situ of monomers including crosslinking monomer whichforms crosslinks during the polymerisation reaction. Where thepolymerisation is a condensation process, tri- and higher-functionalmonomers are used to achieve branching and crosslinking. Where, as ispreferred, the monomers are ethylenically unsaturated and polymerisableby free radical initiated polymerisation, a crosslinking monomer is adi-, tri- or higher-functional ethylenically unsaturated monomer. Thecoating is thus formed by application of a liquid polymerisation mixtureonto the implant surface followed by initiation of polymerisation undersuitable radical generating conditions.

For optimum control of the polymer product, however, it is preferred fora crosslinkable polymer to be presynthesised, used to coat the implantand, after coating, subjected to conditions under which crosslinkingtakes place. The crosslinkable polymers are generally formed frommonomers including pendant reactive groups which do not react under thepolymerisation conditions, but only later under the subsequentcrosslinking conditions. Such conditions may involve application ofheat, for instance raising the coating to a temperature in the range 40to 70° C., in the presence of moisture, for instance at at least 50%relative humidity.

Most preferably the polymer is formed from ethylenically unsaturatedmonomers including a zwitterionic monomer. Preferably the ethylenicallyunsaturated monomers include a surface binding monomer, usually ahydrophobic comonomer. For forming a crosslinkable polymer, theethylenically unsaturated monomers preferably include one or morereactive monomer having a pendant reactive group(s) capable of formingintermolecular crosslinks.

Preferably the zwitterionic monomer has the general formula I:YBX  Iwherein

B is a straight or branched alkylene (alkanediyl), alkyleneoxaalkyleneor alkylene oligo-oxaalkylene chain optionally containing one or morefluorine atoms up to and including perfluorinated chains or, if X or Ycontains a terminal carbon atom bonded to B, a valence bond;

X is a zwitterionic group; and

Y is an ethylenically unsaturated polymerisable group selected from

CH₂═C(R)CH₂O—, CH₂═C(R)CH₂OC(O)—, CH₂═C(R)OC(O)—, CH₂═C(R)O—,CH₂═C(R)CH₂OC(O)N(R¹)—, R²OOCCR═CRC(O)O—, RCH═CHC(O)O—,RCH═C(COOR²)CH₂C(O)O—,

wherein:

R is hydrogen or a C₁-C₄ alkyl group;

R¹ is hydrogen or a C₁-C₄ alkyl group or R¹ is —B—X where B and X are asdefined above; and

R² is hydrogen or a C₁₋₄ alkyl group;

A is —O— or —NR¹—;

K is a group —(CH₂)POC(O)—, —(CH₂)_(p)C(O)O—, —(CH₂)POC(O)O—,—(CH₂)_(p)NR³—, —(CH₂)_(p)NR³C(O)—, —(CH₂)PC(O)NR³—,—(CH₂)_(p)NR³C(O)O—, —(CH₂)_(p)OC(O)NR³—, —(CH₂)_(p)NR³C(O)NR³— (inwhich the groups R³ are the same or different), —(CH₂)_(p)O—,—(CH₂)_(p)SO₃—, or, optionally in combination with B, a valence bond

p is from 1 to 12; and

R³ is hydrogen or a C₁-C₄ alkyl group.

In group X, the atom bearing the cationic charge and the atom bearingthe anionic charge are generally separated by 2 to 12 atoms, preferably2 to 8 atoms, more preferably 3 to 6 atoms, generally including at least2 carbon atoms.

Preferably the cationic group in zwitterionic group X is an amine group,preferably a tertiary amine or, more preferably, a quaternary ammoniumgroup. The anionic group in X may be a carboxylate, sulphate,sulphonate, phosphonate, or more preferably, phosphate group. Preferablythe zwitterionic group has a single monovalently charged anionic moietyand a single monovalently charged cationic moiety. A phosphate group ispreferably in the form of a diester.

Preferably, in a pendant group X, the anion is closer to the polymerbackbone than the cation.

Alternatively group X may be a betaine group (ie in which the cation iscloser to the backbone), for instance a sulpho-, carboxy- orphospho-betaine. A betaine group should have no overall charge and ispreferably therefore a carboxy- or sulpho-betaine. If it is aphosphobetaine the phosphate terminal group must be a diester, i.e., beesterified with an alcohol. Such groups may be represented by thegeneral formula II—X¹—R⁴—N⁺(R⁵)₂—R⁶—V  II

in which X¹ is a valence bond, —O—, —S— or —NH—, preferably —O—;

V is a carboxylate, sulphonate or phosphate (diester-monovalentlycharged) anion;

R⁴ is a valence bond (together with X¹) or alkylene —C(O)alkylene- or—C(O)NHalkylene preferably alkylene and preferably containing from 1 to6 carbon atoms in the alkylene chain;

the groups R⁵ are the same or different and each is hydrogen or alkyl of1 to 4 carbon atoms or the groups R⁵ together with the nitrogen to whichthey are attached form a heterocyclic ring of 5 to 7 atoms; and

R⁶ is alkylene of 1 to 20, preferably 1 to 10, more preferably 1 to 6carbon atoms.

One preferred sulphobetaine monomer has the formula II

where the groups R⁷ are the same or different and each is hydrogen orC₁₋₄ alkyl and d is from 2 to 4.

Preferably the groups R⁷ are the same. It is also preferable that atleast one of the groups R⁷ is methyl, and more preferable that thegroups R⁷ are both methyl.

Preferably d is 2 or 3, more preferably 3.

Alternatively the group X may be an amino acid moiety in which the alphacarbon atom (to which an amine group and the carboxylic acid group areattached) is joined through a linker group to the backbone of polymer A.Such groups may be represented by the general formula IV

in which X² is a valence bond, —O—, —S— or —NH—, preferably —O—,

R⁹ is a valence bond (optionally together with X²) or alkylene,—C(O)alkylene- or —C(O)NHalkylene, preferably alkylene and preferablycontaining from 1 to 6 carbon atoms; and

the groups R⁸ are the same or different and each is hydrogen or alkyl of1 to 4 carbon atoms, preferably methyl, or two of the groups R⁸,together with the nitrogen to which they are attached, form aheterocyclic ring of from 5 to 7 atoms, or the three group R⁸ togetherwith the nitrogen atom to which they are attached form a fused ringstructure containing from 5 to 7 atoms in each ring.

X is preferably of formula V

in which the moieties X³ and X⁴, which are the same or different, are—O—, —S—, —NH— or a valence bond, preferably —O—, and W⁺ is a groupcomprising an ammonium, phosphonium or sulphonium cationic group and agroup linking the anionic and cationic moieties which is preferably aC₁₋₁₂-alkanediyl group.

Preferably W contains as cationic group an ammonium group, morepreferably a quaternary ammonium group.

The group W⁺ may for example be a group of formula —W¹—N⁺R¹⁰ ₃ —W¹—P⁺R¹¹₃, —W¹—S⁺R¹¹ ₂ or —W¹-Het⁺ in which:

W¹ is alkanediyl of 1 or more, preferably 2-6 carbon atoms optionallycontaining one or more ethylenically unsaturated double or triple bonds,disubstituted-aryl, alkylene aryl, aryl alkylene, or alkylene arylalkylene, disubstituted cycloalkyl, alkylene cycloalkyl, cycloalkylalkylene or alkylene cycloalkyl alkylene, which group W¹ optionallycontains one or more fluorine substituents and/or one or more functionalgroups; and

either the groups RIO are the same or different and each is hydrogen oralkyl of 1 to 4 carbon atoms, preferably methyl, or aryl, such as phenylor two of the groups R¹⁰ together with the nitrogen atom to which theyare attached form a heterocyclic ring containing from 5 to 7 atoms orthe three groups R¹⁰ together with the nitrogen atom to which they areattached form a fused ring structure containing from 5 to 7 atoms ineach ring, and optionally one or more of the groups R¹⁰ is substitutedby a hydrophilic functional group, and

the groups R¹¹ are the same or different and each is R¹⁰ or a groupOR¹⁰, where R¹⁰ is as defined above; or

Het is an aromatic nitrogen-, phosphorus- or sulphur-, preferablynitrogen-, containing ring, for example pyridine.

Preferably W¹ is a straight-chain alkanediyl group, most preferablyethane-1,2-diyl.

Preferred groups X of the formula V are groups of formula VI:

where the groups R¹² are the same or different and each is hydrogen orC₁₋₄ alkyl, and e is from 1 to 4.

Preferably the groups R¹² are the same. It is also preferable that atleast one of the groups R¹² is methyl, and more preferable that thegroups R¹² are all methyl.

Preferably e is 2 or 3, more preferably 2.

Alternatively the ammonium phosphate ester group VIII may be replaced bya glycerol derivative of the formula VB, VC or VD defined in our earlierpublication no WO-A-93/01221.

Preferably the surface binding comonomer has the general formula VIIY¹R¹³  VIIwherein Y¹ is selected from

CH₂═C(R¹⁴)CH₂O—, CH₂═C(R¹⁴)CH₂OC(O)—, CH₂═C(R¹⁴)OC(O)—, CH₂═C(R¹⁴)O—,CH₂═C(R¹⁴)CH₂OC(O)N(R¹⁵)—, R¹⁶OOCCR¹⁴═CR¹⁴C(O)O—, R¹⁴CH═CHC(O)O—,R¹⁴CH═C(COOR¹⁶)CH₂C(O)—O—,

wherein:

R¹⁴ is hydrogen or a C₁-C₄ alkyl group;

R¹⁵ is hydrogen or a C₁-C₄ alkyl group or R¹⁵ is R¹³;

R¹⁶ is hydrogen or a C₁₋₄ alkyl group;

A¹ is —O— or —NR¹⁵—; and

K¹ is a group —(CH₂)_(q)OC(O)—, —(CH₂)_(q)C(O)O—, (CH₂)_(q)OC(O)O—,—(CH₂)_(q)NR¹⁷—, —(CH₂)_(q)NR¹⁷C(O)—, —(CH₂)_(q)C(O)NR¹⁷—,—(CH₂)_(q)NR¹⁷C(O)O—, —(CH₂)_(q)OC(O)NR¹⁷—, —(CH₂)_(q)NR¹⁷C(O)NR¹⁷— (inwhich the groups R¹⁷ are the same or different), —(CH₂)_(q)O—,—(CH₂)_(q)SO₃—, or a valence bond

p is from 1 to 12;

and R¹⁷ is hydrogen or a C₁-C₄ alkyl group;

and R¹³ is a surface binding group, selected from hydrophobic groups andionic groups.

In the comonomer of the general formula VII, the group R¹³ is preferablya hydrophobic group, preferably:

a) a straight or branched alkyl, alkoxyalkyl or oligoalkoxyalkyl chaincontaining 6 or more, preferably 6 to 24 carbon atoms, unsubstituted orsubstituted by one or more fluorine atoms optionally containing one ormore carbon double or triple bonds; or

b) a siloxane group —(CR¹⁸ ₂)_(qq)(SiR¹⁹ ₂)(OSiR¹⁹ ₂)_(pp)R¹⁹ in whicheach group R¹⁸ is the same or different and is hydrogen or alkyl of 1 to4 carbon atoms, or aralkyl, for example benzyl or phenethyl, each groupR¹⁹ is alkyl of 1 to 4 carbon atoms, qq is from 1 to 6 and pp is from 0to 49

Most preferably R¹³ is a straight alkyl having 8 to 18, preferably 12 to16 carbon atoms.

The reactive monomer to which provides crosslinkability preferably hasthe general formula VIIIY²B²R²⁰  VIIIwherein

B² is a straight or branched alkylene, oxaalkylene or oligo-oxaalkylenechain optionally containing one or more fluorine atoms up to andincluding perfluorinated chains, or B² is a valence bond;

Y² is an ethylenically unsaturated polymerisable group selected from

CH₂═C(R²¹)CH₂—O—, CH₂═C(R²¹)CH₂OC(O)—, CH₂═C(R²¹)OC(O)—, CH₂═C(R²¹)O—,CH₂═C(R²¹)CH₂OC(O)N(R²²)—, R²³OOCCR²¹═CR²¹C(O)—, R²¹H═CHC(O)O—,R²¹H═C(COOR²³)CH₂C(O)O—

where

R²¹ is hydrogen or C₁-C₄ alkyl;

R²³ is hydrogen, or a C₁₋₄-alkyl group;

A² is —O— or —NR²²—;

R²² is hydrogen or a C₁-C₄ alkyl group or R²² is a group B²R²⁰;

K² is a group —(CH₂)_(k)OC(O)—, —(CH)_(k)C(O)O—, —(CH₂)_(k)OC(O)O—,—(CH₂)_(k)NR²²—, —(CH₂)_(k)NR²²C(O)—, —(CH₂)_(k)OC(O)O—,—(CH₂)_(k)NR²²—, —(CH₂)_(k)NR²²C(O)—, —(CH₂)_(k)C(O)NR²²—,—(CH₂)_(k)NR²²C(O)O—, —(CH₂)_(k)OC(O)NR²²—, —(CH₂)_(k)NR²²C(O)NR²²— (inwhich the groups R²² are the same or different), —(CH₂)_(k)O—,—(CH₂)_(k)SO₃—, a valence bond and k is from 1 to 12; and

R²⁰ is a cross-linkable group.

Group R²⁰ is selected so as to be reactive with itself or with afunctional group in the polymer (eg in group R¹³) or at a surface to becoated. The group R²⁰ is preferably a reactive group selected from thegroup consisting of ethylenically and acetylenically unsaturated groupcontaining radicals; aldehyde groups; silane and siloxane groupscontaining one or more substituents selected from halogen atoms andC₁₋₄-alkoxy groups; hydroxyl; amino; carboxyl; epoxy; —CHOHCH₂Hal (inwhich Hal is selected from chlorine, bromine and iodine atoms);succinimido; tosylate; triflate; imidazole carbonyl amino; optionallysubstituted triazine groups; acetoxy; mesylate; carbonyl di(cyclo)alkylcarbodiimidoyl; isocyanate, acetoacetoxy; and oximino. Most preferablyR²⁰ comprises a silane group containing at least one, preferably threesubstituents selected from halogen atoms and C₁₋₄-alkoxy groups,preferably containing three methoxy groups.

Preferably each of the groups Y to Y² is represented by the same type ofgroup, most preferably each being an acrylic type group, of the formulaH₂C═C(R)C(O)-A, H₂C═C(R¹⁴)C(O)A¹ or H₂C═C(R²¹)C(O)-A², respectively.Preferably the groups R, R¹⁴ and R²¹ are all the same and are preferablyH or, more preferably, CH₃. Preferably A, A¹ and A² are the same and aremost preferably —O—. B and B² are preferably straight chainC₂₋₆-alkanediyl.

Preferably the ethylenically unsaturated comonomers comprise diluentcomonomers which may be used to give the polymer desired physical andmechanical properties. Particular examples of diluent comonomers includealkyl(alk)acrylate preferably containing 1 to 24 carbon atoms in thealkyl group of the ester moiety, such as methyl(alk)acrylate or dodecylmethacrylate; a dialkylamino alkyl(alk)acrylate, preferably containing 1to 4 carbon atoms in each alkyl moiety of the amine and 1 to 4 carbonatoms in the alkylene chain, e.g. 2-(dimethylamino)ethyl(alk)acrylate;an alkyl (alk)acrylamide preferably containing 1 to 4 carbon atoms inthe alkyl group of the amide moiety; a hydroxyalkyl(alk)acrylatepreferably containing from 1 to 4 carbon atoms in the hydroxyalkylmoiety, e.g. a 2-hydroxyethyl (alk)acrylate glycerylmonomethacrylate orpolyethyleneglycol monomethacrylate; or a vinyl monomer such as anN-vinyl lactam, preferably containing from 5 to 7 atoms in the lactamring, for instance vinyl pyrrolidone; styrene or a styrene derivativewhich for example is substituted on the phenyl ring by one or more alkylgroups containing from 1 to 6, preferably 1 to 4, carbon atoms, and/orby one or more halogen, such as fluorine atoms, e.g.(pentafluorophenyl)styrene.

Other suitable diluent comonomers include polyhydroxyl, for examplesugar, (alk)acrylates and (alk)acrylamides in which the alkyl groupcontains from 1 to 4 carbon atoms, e.g. sugar acrylates, methacrylates,ethacrylates, acrylamides, methacrylamides and ethacrylamides. Suitablesugars include glucose and sorbitol. Diluent comonomers includemethacryloyl glucose and sorbitol methacrylate.

Further diluents which may be mentioned specifically includepolymerisable alkenes, preferably of 2-4 carbon atoms, eg. ethylene,dienes such as butadiene, ethylenically unsaturated dibasic acidanhydrides such as maleic anhydride and cyano-substituted alkenes, suchas acrylonitrile.

Particularly preferred diluent monomers are nonionic monomers, mostpreferably alkyl(alk)acrylates or hydroxyalkyl(alk)acrylates.

It is particularly desirable to include hydroxyalkyl(alk)acrylates incombination with reactive comonomers which contain reactive silylmoieties including one or more halogen or alkoxy substituent. Thehydroxyalkyl group containing monomer may be considered a reactivemonomer although it also acts as a diluent. Such reactive silyl groupsare reactive with hydroxy groups to provide crosslinking of the polymerafter coating, for instance.

A particularly preferred combination of reactive monomers isω(trialkoxysilyl)alkyl(meth)acrylate and anω-hydroxyalkyl(meth)acrylate.

Preferably the zwitterionic monomer is used in the monomer mixture in amolar proportion of at least 1%, preferably less than 75%, morepreferably in the range 5 to 50%, most preferably 10-33%. The surfacebinding comonomer is generally used in molar proportion of at least 2%,preferably at least 5% or at least 10%, more preferably in the range 15to 99%. Where the surface binding monomer comprises hydrophobicphysisorbable groups, it is preferably present in a molar amount in therange 30 to 99%. Where the polymer is not covalently bonded to thesubstrate or cross-linked, the amount of hydrophobic surface bindingmonomer is preferably in the range 50 to 95%, more preferably 60 to 90%.The cross-linkable monomer is preferably used in a molar amount in therange 2 to 33%, preferably 3 to 20%, more preferably 5 to 10% by mole.

The zwitterionic polymer can be represented by the general formula IX:

in which l is 1 to 75, m is 0 to 99, n is 0 to 33 and m+n is 25 to 99,Y³ to Y⁵ are the groups derived from Y to Y², respectively, of theradical initiated addition polymerisation of the ethylenic group in Y toY², and

B and X are as defined for the general formula I,

R¹³ is as defined for the general formula VII, and

B² and R²⁰ are as defined for the general formula VIII.

In the preferred zwitterionic polymer in which Y, Y¹ and Y² are eachacrylic groups the polymer has the general formula X

in which B, X, R and A are as defined for the compound of the generalformula I, R¹⁴, A¹ and R¹³ are as defined for the general formula VII,R²¹, D², B² and R²⁰ are as defined for the general formula VIII and I, mand n are as defined for the general formula IX

The polymerisation is carried out using suitable conditions as known inthe art. Thus the polymerisation involves radical initiation, usingthermal or redox initiators which generate free radicals and/or actinic(e.g. u.v or gamma) radiation, optionally in combination withphotoinitiators and/or catalysts. The initiator is preferably used in anamount in the range 0.05 to 5% by weight based on the weight of monomerpreferably an amount in the range 0.1 to 3%, most preferably in therange 0.5 to 2%. The level of initiator is generally higher where themonomer includes reactive monomer and the polymer is cross-linkable, eg1 to 20%.

The molecular weight of the polymer (as coated, where the polymer iscross-linkable) is in the range 1×10⁴ to 1×10⁶, preferably in the range5×10⁴ to 5×10⁵ D.

The monomer mixture and the monomer mixture may include anon-polymerisable diluent, for instance a polymerisation solvent. Such asolvent may provide solubility and miscibility of the monomers. Thesolvent may be aqueous or non-aqueous. The polymer may be recovered byprecipitation from the polymerisation mixture using a precipitatingsolvent, or recovery may involve removal of any non polymerisablediluent by evaporation, for instance.

The implant used in the invention is generally for substantiallypermanent implantation. It may be formed of a polymeric, for instance asynthetic polymeric, material or, preferably, is formed of metal. Thedevice may be a catheter, a graft or a stent graft, but is preferably astent, generally a permanent stent. The stent is suitable for use forinsertion into any body lumen, such as of the urinary tract, or GItract. Preferably it is suitable for implantation into a blood vessel,especially a coronary blood vessel.

According to a further aspect of the invention an implant selected froma graft, a stent and a stent-graft having a polymer matrix coating onits inner and outer surfaces, is loaded with a pharmaceutical active byswelling the polymer matrix in a solution of the active, and ischaracterised further in that the polymer of the matrix is across-linked polymer formed from ethylenically unsaturated monomerincluding

a) a zwitterionic monomer of the general formula IYBX  Iwherein

B is a straight or branched alkylene (alkanediyl), alkyleneoxaalkyleneor alkylene oligo-oxaalkylene chain optionally containing one or morefluorine atoms up to and including perfluorinated chains or, if X or Ycontains a terminal carbon atom bonded to B, a valence bond;

X is a zwitterionic group; and

Y is an ethylenically unsaturated polymerisable group selected from

CH₂═C(R)CH₂O—, CH₂═C(R)CH₂OC(O)—, CH₂═C(R)OC(O)—, CH₂═C(R)O—,CH₂═C(R)CH₂OC(O)N(R¹)—, R²OOCCR═CRC(O)O—, RCH═CHC(O)O—,RCH═C(COOR²)CH₂C(O)O—,

wherein:

R is hydrogen or a C₁-C₄ alkyl group;

R¹ is hydrogen or a C₁-C₄ alkyl group or R¹ is —B—X where B and X are asdefined above; and

R² is hydrogen or a C₁₋₄ alkyl group;

A is —O— or —NR¹—;

K is a group —(CH₂)_(p)OC(O)—, —(CH₂)_(p)C(O)O—, —(CH₂)_(p)OC(O)O—,—(CH₂)_(p)NR³, —(CH₂)_(p)NR³C(O)—, —(CH₂)_(p)C(O)NR³—,—(CH₂)_(p)NR³C(O)O—, —(CH₂)_(p)OC(O)NR³—, —(CH₂)_(p)NR³C(O)NR³— (inwhich the groups R³ are the same or different), —(CH₂)_(p)O—,—(CH₂)_(p)SO₃—, or, optionally in combination with B, a valence bond

p is from 1 to 12; and

R³ is hydrogen or a C₁-C₄ alkyl group;

b) a surface binding monomer of the general formula VIIY¹R¹³  VIIwherein Y¹ is selected from

CH₂═C(R¹⁴)CH₂O—, CH₂═C(R¹⁴)CH₂OC(O)—, CH₂═C(R¹⁴)OC(O)—, CH₂═C(R¹⁴)O—,CH₂═C(R¹⁴)CH₂OC(O)N(R¹⁵)—, R¹⁶OOCCR¹⁴═CR¹⁴C(O)O—, R¹⁴CH═CHC(O)O—,R¹⁴CH═C(COOR¹⁶)CH₂C(O)—O—,

wherein:

R¹⁴ is hydrogen or a C₁-C₄ alkyl group;

R¹⁵ is hydrogen or a C₁-C₄ alkyl group or R¹⁵ is R¹³;

R¹⁶ is hydrogen or a C₁₋₄ alkyl group;

A¹ is —O— or —NR¹⁵—; and

K¹ is a group —(CH₂)_(q)OC(O)—, —(CH₂)_(q)C(O)O—, (CH₂)_(q)OC(O)O—,—(CH₂)_(q)NR¹⁷—, —(CH₂)_(q)NR¹⁷C(O)—, —(CH₂)_(q)C(O)NR¹⁷—,—(CH₂)_(q)NR¹⁷C(O)O—, —(CH₂)_(q)OC(O)NR¹⁷—, (CH₂)_(q)NR¹⁷C(O)NR¹⁷— (inwhich the groups R¹⁷ are the same or different), —(CH₂)_(q)O—,—(CH₂)_(q)SO₃—, or a valence bond

p is from 1 to 12;

and R¹⁷ is hydrogen or a C₁-C₄ alkyl group;

and R¹³ is a surface binding group, selected from hydrophobic groups andionic groups; and

c) a reactive monomer of the general formula VIIIY²B²R²⁰  VIIIwherein

B² is a straight or branched alkylene, oxaalkylene or oligo-oxaalkylenechain optionally containing one or more fluorine atoms up to andincluding perfluorinated chains, or B² is a valence bond;

Y² is an ethylenically unsaturated polymerisable group selected from

CH₂═C(R²¹)CH₂—O—, CH₂═C(R²¹)CH₂OC(O)—, CH₂═C(R²¹)OC(O)—, CH₂═C(R²¹)O—,CH₂═C(R²¹)CH₂OC(O)N(R²²)—, R²³OOCCR²¹═CR²¹C(O)O—, R²¹H═CHC(O)O—,R²¹H═C(COOR²³)CH₂C(O)O—

where

R²¹ is hydrogen or C₁-C₄ alkyl;

R²³ is hydrogen, or a C₁₋₄-alkyl group;

A² is —O— or —NR²²—;

R²² is hydrogen or a C₁-C₄ alkyl group or R²² is a group B²R²⁰;

K² is a group —(CH₂)_(k)OC(O)—, —(CH)_(k)C(O)O—, —(CH₂)_(k)OC(O)O—,—(CH₂)_(k)NR²²—, —(CH₂)_(k)NR²²C(O)—, —(CH₂)_(k)OC(O)O—,—(CH₂)_(k)NR²²—, —(CH₂)_(k)NR²²C(O)—, —(CH₂)_(k)C(O)NR²²—,—(CH₂)_(k)NR²²C(O)O—, —(CH₂)_(k)OC(O)NR²²—, —(CH₂)_(k)NR²²C(O)NR²²— (inwhich the groups R²² are the same or different), —(CH₂)_(k)O—,—(CH₂)_(k)SO₃—, a valence bond and k is from 1 to 12; and

R²⁰ is a silyl group having three alkoxy substituents.

Preferably the polymer also comprises a further reactive monomer of theformula VIII, in which R²⁰ is a hydroxyl group.

Such polymers are cross-linked by heating. The polymers preferably havethe monomer ratios mentioned above, and are synthesised and coated usingthe above described techniques.

The polymer matrix coatings are stable to conditions used duringsterilisation techniques. For instance sterilisation may be carried outby ethylene oxide or gamma irradiation. Following sterilisation theproduct device is usually packaged for storage, transportation to ahospital or surgery etc. It is an advantage of the present inventionthat a stent provided with a polymer matrix coating is suitable for useas a delivery device for a range of pharmaceutical actives. The choiceof pharmaceutical active may thus lie with the medical practitioner,determined upon the basis of his diagnosis.

The step of swelling the coating is carried out by dipping the polymermatrix coated device into the solution, by spraying the device with thesolution or a combination of dipping and spraying. The dipping andspraying may be carried out intermittently, for instance with dryingphases between the immersion or spraying phases.

It is particularly preferred that the polymer matrix coated on the outersurface of the implant has a coating thickness 1.5 to 50 times that ofthe polymer matrix on the interior wall surface, more preferably atleast 2 times that of the thickness of the coating on the interior wallsurface.

A coating on a stent can be considered a monolith for the purposes ofcalculating the release of a drug. Release is governed by equation 1(Baker, R W et al in “Controlled Release of Biologically Active Agents,15, Tanquary A C and Lacey R E (Eds) Plenum Press, NY (1973)):

$\begin{matrix}{\frac{M_{t}}{M_{\overset{\_}{o}}} = {{4\left\{ \frac{D\; t}{\pi\mspace{11mu} l^{\; 2}} \right\}^{0.5}\mspace{14mu}{where}\mspace{14mu} 0} \leq {M_{t}/M_{\overset{\_}{o}}} < 0.}} & {{Equation}\mspace{14mu} 1}\end{matrix}$

in which M_(t) is the mass of drug release after time t, m is the totalamount of drug which can be released, I is the thickness of the coatingand D is the coefficient of diffusion of the drug in the polymer matrix.

It can be seen that the half life varies with the square of thethickness. In the present invention the swollen thickness of the polymermatrix/pharmaceutical active coating in the product device is in therange 100 nm to 1000 μm, most preferably in the range 200 nm to 100 μm.The thickness of the polymer matrix before swelling is preferably in therange 20 nm to 1 mm, preferably 50 nm to 500 μm, for instance more than500 nm at least on the exterior surface, and less than 5 μm.

The polymer/pharmaceutical active combination is selected so as to givesuitable release rates, as desired. Furthermore, the release half life,and consequently period over which the pharmaceutical active will bereleased, may be controlled by selection of a suitable coatingthickness. The diffusion coefficient can be calculated by experiment,for instance following the techniques used in the examples below. Thesuitable thickness can be calculated from the desired total loadinglevels and rate of delivery required, from equation 1 above.

The solvent in the pharmaceutical active containing solution used toload the polymer matrix coating is selected for its compatibility withthe polymer and with the pharmaceutical active. Thus it must be asolvent for the pharmaceutical active and the solution must swell thepolymer matrix at a convenient rate.

The period over which the polymer matrix coating is swollen in thepharmaceutical active containing solution is preferably no more 24hours, most preferably less than 12 hours, for instance less than 3hours, most preferably less than 30 minutes. The period is usually morethan 30 s, usually more than 1 minute, for instance 5 minutes or more.

Swelling is conducted at ambient temperature, for instance around 20 to25° C., or at raised temperature, for instance body temperature, 37° C.The polymers generally swell faster at higher temperatures, for instanceat 37° C. The rate of swelling of the polymer matrix depends also on thediffusion coefficient of the solvent in the polymer, which in turndepends upon the nature of the polymer including its level ofcrosslinking. The thickness of the coating also affects the period overwhich the swelling step should take place. The pharmaceutical active,the solute in the solution, may also affect the rate of swelling of thepolymer in the solution. These parameters can be determined andoptimised empirically.

In the invention it is preferred that the pharmaceutical-loaded coatingbe continuous over the coated surface. Preferably it should be ofsubstantially uniform thickness on the or each surface coated. Where theproduct is a stent, or a graft, it is particularly preferred for thecoating to be on both sides of the device, but that it be of differentthickness on the inside to the outside of the device. It is preferredthat a larger reservoir of drug be provided on the outer surface whereit is released directly into the tissue with which it is in contactduring use. Since systemic delivery is generally to be minimised, atleast in the long term, the coating on the inner surface is preferablythin.

The ratio of thicknesses between the exterior and interior wall surfacesof a stent or a graft is generally (at least 1.5):1, preferably (atleast 2):1 and often higher than this, for instance (up to 10):1 ormore, eg (up to 50):1. It is desirable that the interior wall surface beprovided with a coating of polymer matrix to provide biocompatibility,especially non-thrombogenicity.

A thicker coating of the polymeric matrix may be provided on the outersurface of a stent or a graft by selection of a suitable coatingtechnique. For a stent, which has openings in its tubular wall, coatingof optimum uniformity is achieved by a dipping process. To achieve alower coating thickness on the inner surface in the product, liquidcoating may be removed from the inner surface prior to drying, forinstance by directing a flow of fluid through the inner lumen, generallyof gas, for instance air. Preferably coating is carried out as describedin WO-A-0004999, to provide a thinner coating on the interior wall ascompared to the exterior wall.

The choice of the solvent is governed by the rate of swelling of thepolymer matrix, the solubility characteristics of the pharmaceuticalactive as well as the pharmaceutical acceptability. The solvent issuitably, for instance, an alcohol, including a glycol, water ormixtures thereof. An alcohol is preferably a lower alkanol, for instanceethanol or isopropanol. Most preferably the solvent is aqueous.

The pharmaceutical active solution may contain ingredients such assalts, buffers, pH modifying agents, dyes, etc.

Equilibrium swelling of the polymer matrix coated implant may bedetermined by monitoring the rate of progress of swelling after contactof the implant with the pharmaceutical active solution, for instance byremoving the partially swollen device, drying off residual solvent andmonitoring the gain in weight. The equilibrium swelling may,alternatively, be calculated from a knowledge of the swellability of thepolymer matrix itself in the respective solution at 37° C., and thethickness of the coating on the implant, using formula 1 above. Whilstthe equilibrium swelling may be affected by the nature of thepharmaceutical active, it is generally substantially the same as theequilibrium swelling in the solvent excluding the drug, especially wherethe drug is uncharged. The equilibrium swelling can thus be determinedor calculated from the swelling in the solvent itself, generallyincluding any salt or buffer.

We believe that the provision of a stent having a coating comprisingpolymer and elutable pharmaceutical active on interior and exteriorwalls in which the thickness of the polymer coating on the exterior wallof the stent is at least 1.5 times the thickness of the coating on theinterior wall, is novel and forms a further aspect of the invention. Inthis aspect, the stent is for temporary or, more preferably, permanentimplantation into a body lumen, and is formed of an impermeablegenerally tubular body having an interior and an exterior wall, theimpermeable material of the body being substantially entirely coatedwith a biocompatible coating. The is preferably formed of metal, and maybe formed of wire, for instance by braiding or other shaping means intoa tube shape. Preferably the stent is formed from a tube by cutting oretching through the thickness of the tube to form openings.

In this aspect of the invention, the pharmaceutical active is a compoundwhich is required to be delivered to the vessel wall in which the stentis to be implanted, but is preferred to be released into the circulationat very low rates. The material of the stent, being metal, isimpermeable to pharmaceutical actives. Accordingly, by providing athicker polymer matrix from which drug is delivered from the exteriorwall as compared to the thickness of the coating on the interior wall,the rate of delivery of drug from the exterior wall into the vesselafter implantation will be optimised, whilst minimising the extent ofdelivery of the pharmaceutical active into the circulation.

In this aspect of the invention, the polymer is present on the stent ata thickness such that the polymer thickness under physiological in useconditions (when swollen with physiological saline at 37° C.) is in therange 100 nm to 100 μm on the exterior wall of the stent. The respectivethickness on the interior wall is lower, and should preferably be lessthan 5 μm. The ratio of thicknesses is preferably as described above.

In this aspect of the invention, the polymer is a material which, whenin contact with aqueous fluids, is permeable to the pharmaceuticalactive. The polymer should preferably be a water-swellable material.

The polymer may be any biocompatible polymer which has been used toprovide biocompatible coatings on stents or other implants. Preferablythe polymer is biostable and hence water-insoluble, for instancebiodegradable or bioerodable polymers. Preferably the polymer iswater-swellable, since the diffusion of solvents through hydrogels iscontrollable and such materials provide controlled release deliverysystems. The polymer may, for instance, be a silicone hydrogel, apolyurethane, or polyethers, such as polyethylene glycol, polyamides,polyesters, such as hydroxy-butyric acid polymers and copolymers,poly(lactides) or polyacrylic polymers. Preferably the polymer iscrosslinked zwitterionic polymer, most preferably a polymer of the typedescribed above in connection with the first and second aspect of theinvention.

In this aspect of the invention, the stent may be provided withpharmaceutical active preloaded into the polymer matrix, rather thanbeing loaded immediately before by a surgeon. The polymer may be mixedwith drug before coating on to the stent. Where the polymer in theproduct is cross-linked, the coating composition preferably containscross-linkable polymer, which is cross-linked after coating, ie in thepresence of the drug. We have found that low molecular weight actives,for instance having molecular weight up to about 1200 D, are releasedfrom such coatings, at approximately the same rate as the drug loaded inthe preformed coating.

The polymer/pharmaceutical active coating is preferably in an unswollenstate when supplied ready for use. The stent may be preloaded onto adelivery catheter, or may be loaded by the surgeon onto such catheterimmediately before use. In either event, the stent may be delivered dryinto the body passageway of a patient or, alternatively, may be wettedwith saline or an aqueous solution of another pharmaceutical active.

Alternatively, the stent with loaded pharmaceutical active anddifferential polymer matrix thickness may be produced immediately beforeuse by dipping a suitable polymer coated stent into a loading solutionof a pharmaceutical active. In this case, the polymer coated stent maybe pre-mounted on a delivery catheter or may be mounted onto such adevice after loading of the pharmaceutical active. Preferably theloading is carried out as described above by swelling the polymer coatedstent in a aqueous pharmaceutical active solution to swell at leastpartially the polymer coating, followed by optional drying prior todelivery into a patient.

The pharmaceutical active used in all aspects of the present inventionis preferably selected from the following classes of drugs:anti-proliferatives, such as growth factor antagonists, migrationinhibitors, somatostatin analogues, ACE-inhibitors, and lipid-loweringdrugs; anti-coagulants, such as direct anti-coagulants which inhibit theclotting cascade, indirect anti-coagulants, which depress the synthesisof clotting factors, anti-platelet (aggregation) drugs, such asthromboxane A2 inhibitors or antagonists, adenosine inhibitors,glycoprotein receptor Iib/IIIa antagonists, thrombin inhibitors;vasodilators, including vasoconstriction antagonists, such as ACEinhibitors, angiotensin II receptor antagonists, serotonin receptorantagonists, and thromboxane A2 synthetase inhibitors, and othervasodilators; anti-inflammatories; cytotoxic agents, such asanti-neoplastic agents, alkylating agents, anti-metabolites, mitoticinhibitors, and antibiotic antineoplastic agents; and radioactive agentsor targets thereof, for local radiation therapy. The active is mostpreferably an anti-angiogenic compound, for instance an antithromboticcompound and/or an anti-proliferative agent. Suitable examples ofpharmaceutical actives include dipyrimadole, angiopeptin, rapamycin,roxithromycin, etoposide, aspirin and dexamethasone.

The following examples illustrate the invention:

EXAMPLE 1 HEMA-PC-co-LM 1:2 Copolymer

A polymer was synthesised by copolymerising 1 part (mole)2-methacryloyloxyethyl-2′-trimethylammoniumethyl phosphate inner saltwith 2 parts dodecylmethacrylate, according to the technique of example1 of WO-A-93/01221. The copolymer is subsequently used in the examplesbelow.

EXAMPLE 2 Drug Delivery from HEMA-PC-co-LM 1:2 Copolymer

The implants tested were commercially available Johnson & JohnsonPalmaz-Schatz stents. These were coated by dipping them in solutionscontaining 100 mg/ml of HEMA-PC-co-LM 1:2 produced in example 1.

Caffeine Loading

Initial stent loading was performed by swelling the coated stents inaqueous solutions of caffeine (10 mg/ml).

Drug release into an aqueous medium was followed spectrophotometricallyusing a temperature-controlled Caleva Dissolution Tester and a Cecil9620 continuous flow UV-spectrophotometer. Results indicated thepresence of low levels of drug, around 0.025 mg per stent. Release timeswere negligible, indicating a “burst effect of caffeine from thecoating”.

An additional experiment was conducted using caffeine in a higherconcentration in the swelling solution, namely 10% w/w. No significantincrease in loading levels or release half life.

Caffeine as a small (molecular weight 194 D) relatively hydrophilic(soluble at 1 g in 46 ml water at room temperature) releases at least80% of its loading in the first 60 seconds. Such drugs are believed tobe unsuitable for loading into zwitterionic polymers, for this reason.

EXAMPLE 3

Crosslinkable quater polymers were made from2-methacryloyloxyethyl-2′-trimethylammoniumethyl phosphate inner salt,dodecylmethacrylate, 3-hydroxypropyl methacrylate and3-(trimethoxysilyl)propyl methacrylate 27:55:15:3 (molar ratios),produced according to example 1-005 of WO-A-98/30615. Further polymerswere formed as follows:

HEMA-PC:2-hydroxyethyl methacrylate:methyl methacrylate:methylene bisacrylamide (MBA) 12.5:67.22:20:0.28.

HEMA-PC:LM (lauryl methacrylate):methylene bis acrylamide (MBA) 1:2 or1:1 HEMA-PC:LM with varying amounts of MBA ranging between 0.28 and 5.0mole %.

HEMA-PC:LM:3-chloro-2-hydroxypropyl methacrylate (20:75:5).

The polymers including MBA were polymerised in situ to form crosslinkedmembranes. The polymers with crosslinkable groups (trimethoxysilylpropylor 3-chloro-2-hydroxypropyl) were coated to form a membrane andsubsequently crosslinked.

The crosslinked polymers were used to form “infinite slabs” typemembranes, to simulate the coating on a stent.

In a first series of experiments, the HEMA-PC:HEMA:MMA:MBA copolymer wasswollen in aqueous solutions of caffeine, dicloxacillin, vitamin B12,rhodamine and dipyridamole in water at room temperature over night.

The loaded levels were established to be the following:

TABLE 1 Drug Loading (mg/g polymer) Caffeine 80 Vitamin B12 40Dicloxacillin 32 Rhodamine 85 Dipyridamole 32

The profile of fractional release against square root of time forrelease into water (using the same equipment as example 2) are set outin FIG. 1. These profiles show that there is a fickian relationshipbetween the fractional release and square root of time for the drugs.Caffeine, however, is released in an initial burst, with substantiallytotal release after about an hour. The more hydrophobic drugs arereleased more slowly.

EXAMPLE 4 Effective Polymer Composition on Release of Dicloxacillin

The membrane formed based on a 1:4 copolymer of HEMA-PC anddodecylmethacrylate (LM) with 2 mole % of reactive monomer which is3-chloro-2-hydroxypropyl methacrylate, was compared to the polymercrosslinked by diethylenically unsaturated monomer MBA used in example 3above, to compare release rates to dicloxacillin, a medium molecularweight model drug. The release rates are shown in FIG. 2 which showsfractional release against square root of time.

The results show that, for the polymer having hydrophobic groups, thehalf life is much higher, even where the swelling figures and loadingswere comparable.

EXAMPLE 5 Experiments on Release from Different Thickness Membranes ofCaffeine

The membrane used in these experiments was that used in example 3 above,based on 0.28 mole % MBA. The membrane thicknesses tested were 0.57 and0.87 mm. The membranes were swollen in an aqueous solution of caffeine.The release profiles are shown in FIG. 3.

EXAMPLE 6 Varying Cross-Linker Level

Polymers based on HEMA-PC:LM 1:2 with varying degrees of MBA crosslinkerwere tested to determine the effect of crosslinker on release of vitaminB12. The polymers were also tested for their water content when swollento equilibrium in water at 37° C. The loading levels of vitamin B12 arerecorded in table 2 below.

Also recorded in table 2 are similar results for MBA crosslinkedcopolymers based upon 1:1 copolymers of HEMA-PC and LM.

TABLE 2 Crosslinker Water Content (%) Vitamin B12 Load HEMA-PC:LM (mole%) (37° C.) (mg/g polymer) 1:2 0.28 56 11.73 0.5 54 10.68 1 52 11.4 2 434.66 5 35 1.96 10 30 0 1:1 0.28 70 26.13 0.5 66 19.83 1 59 11.89 2 558.44 5 47 4.94

The release profile for the 1:1 copolymer series are shown in FIG. 4.

EXAMPLE 7

The quater polymer synthesised as described above is formed into amembrane incured and loaded with caffeine and dipyridamole each fromaqueous and 1:1 ethanol:water solutions, respectively. The releaseprofiles are shown in accompanying FIG. 5.

The half lives may be calculated from FIG. 5 which shows that the halflife for caffeine release is 3 minutes while that for dipyridimole if 5hours. The water content of the membrane when fully swollen in water at37° C. is 56%. The total loading rates for the two model drugs are 28mg/g polymer for caffeine and 18 mg/g polymer for dipyridimole.

EXAMPLE 8

HEMA-PC:LM 1:2 copolymer prepared as described in example 1, theHEMA-PC:LM:hydroxypropyl methacrylate:trimethoxysilylpropyl methacrylatequater polymer produced as in example 3 and an adaptation of the latterpolymer but at mole ratios 27:27:35:12 were used to coat stents. Thestents were biodiv Ysio stents and were coated using a dip coating rigwhich dips the stent and removes it from the coating solution at a rateof 5 mm/second and, after each dip step, dries the stent by sucking airthrough the lumen for about 1 minute. Multiple coatings were formedusing different concentration polymer solutions as shown in thefollowing table. The sucking of air through the central lumen results inlower coating thicknesses on the inside of the stent as shown by table3. The coating solutions were, in each case, in ethanol. After coatingthe stents were dried at 70° C. for 16 hours during which timecrosslinking takes place and subsequently sterilised by gamma radiation.

TABLE 3 Coating Thickness Process(approx.) Stent CoatingSteps/concentration Outside Inside —.2 8 × 25 mg/ml 600 50 —.2 4 × 50mg/ml 1100 600 —.2 2 × 50 mg/ml 800 300 —.3 8 × 25 mg/ml 700 50

Radio-labelled angiopeptin was custom prepared at Amersham Internationaland supplied in an isotonic 0.05 M acetic acid solution at aconcentration of 1 mg/ml. The solution was diluted to 500 μg/ml usingisotonic 0.05 M acetic acid. The coated stents were placed in thesolution and left at 37° C. for 30 minutes. The stents were then removedand allowed to dry at 40° C. for 30 minutes, before gamma counting toobtain total loading.

Water uptake was judged to be over 50% of the total water uptake atequilibrium.

Our results showed that increasing the period over which crosslinkingtakes place, the rate of swelling is reduced.

The quater polymers used in the angiopeptin loading series were set outin table 4 below. The angiopeptin loadings are shown in FIG. 6.

TABLE 4 Series HEMA-PC LM Hpm TMSPM 1 13 39 15 5 53 39 15 5 13 55 15 533 55 15 5 2 13 39 15 9 33 39 15 9 13 55 15 9 33 55 15 9 3 13 39 35 5 3339 35 5 13 55 35 5 33 55 35 5 4 13 39 35 9 33 39 35 9 13 55 35 9 33 5535 9

EXAMPLE 9 Loading Cross-Linked Polymers with Taxol

Polymers of the same compositions as used in example 8 are tested fortaxol (paclitaxel) loading. Twenty discs were cut out of each membraneof polymer, placed on pieces of PTFE in petri dishes and dried in anoven at 60° C. for an hour. When cool the discs were placed into asolution of taxol and allowed to swell in a water bath at 37° C. forhalf an hour. The taxol solution was decanted off, the discs labelledand placed on the PTFE and allowed to air dry. The discs were thentested for determining total loadings. The results are shown in table 5below.

TABLE 5 Total Loading Series: Ex (μg per disc) Standard Deviation 1 35.23 80 8.2 15 2.4 18.1 3 2 51.7 2.4 57 9.8 18.6 2.8 10 14.7 3 55.2 20.211.2 10.6 5.4 3 25.3 5.4 4 23.8 6.8 60.5 2.6 24.3 1.8 64 3.9

EXAMPLE 10 Loading Stents Pre-Coated with Cross-Linked Polymer withRapamycin

Rapamycin is a microlide having immunosuppresive properties. Forinstance it has been shown to have immunosuppresaent activity in ananimal model of allograft rejection, by inhibiting T-cell activation. Ithas also been shown to block CD28-dependent stimulation. It has alsobeen shown to apoptosis of cells by binding to intracellularSK506-binding protein. It has a molecular weight of 913, an a lowsolubility in water (5 mg/l), requiring ethanol in the swelling solutionto assist solubilisation.

In the loading experiments, rapamycin was dissolved in 100% ethanol, atconcentrations of 20, 50 and 55 g/l. Stents provided with the coatingsas described in Reference Example 1 were loaded with rapamycin by beingimmersed in the respective solutions for periods of either 5 minutes or30 minutes. The stents were subsequently removed from the rapamycin andwick dried on an absorbent tissue. The stents were subsequently allowedto dry for 30 minutes or more at room temperature. In addition,separately the stent, preloaded on a balloon catheter, was dipped for 5minutes in the 55 g/l solution, and allowed to dry for 30 minutes atroom temperature.

The loaded stents were subjected to elution studies at 25° C. and 37° C.The tests carried out at 25° C. involved individually placing the stentsin vials containing 5 ml PBS and gently agitating the vials for a periodof up to 2 hours. At time intervals samples of the buffer were testedfor their rapamycin content, using HPLC.

The tests at 37° C. involved a flow system, with a flow of phosphatebuffered saline being passed through channels, each containing onestent, the system being maintained at 37° C. In each channel, 2 stentswere placed and 500 ml PBS were recirculated through the channel at arate of 100 ml/min to minimise the circulation. The level ofconcentration of rapamycin in the solution, and remaining on the stentwas determined.

For the premounted stent, elution studies, were not conducted, but thestent was expanded on the balloon, removed from the catheter andsubjected to a test to determine the level of uptake of rapamycin.

The effects of drug loading time and concentration are shown in thefollowing table 6:

TABLE 6 Unmounted stents Rapamycin Total loading ISD/ concentration inDrug loading Stent μg per stent ethanol (100%) time/minutes size/mm (no.Stents measured) 20 30 18  47 ± 13 (4) 50 5 15 172 ± 5 (2) 55 5 15 142 ±1 (3) 55 30 15  104 ± 20 (3)

The figures indicate that stents loaded from higher drug concentrationsolutions become loaded with higher levels of drugs. They also indicatethat long loading times are not required and that 5 minutes is adequate.

The results of the elution tests using agitated PBS at 20° C. are shownin table 7 below

TABLE 7 Unmounted stents Elution Rapamycin on Cumulative rapamycin TestTime/min stent/μg eluted per stent/μg 9.1 Pre-elution 0 47 ± 3  0 5 — 1.6 ± 0.5 15 —  7.4 ± 1.9 30 — 15.9 ± 3.1 Post-elution 60 37 ± 13 26.2± 3.3 9.2 Pre-elution 0 104 ± 20  0 5 —  1.0 ± 0.1 15 —  4.8 ± 0.2 30 —10.2 ± 0.5 60 — 18.5 ± 1.2 Post-elution 120 84 ± 21 29.2 ± 1.7

The results indicate that there is a slow release of rapamycin over aperiod of 1 to 2 hours. For the stents having the higher initial loading(produced by loading for 30 minutes in a 55 g/l solution), there isstill a high proportion of rapamycin remaining on the stent even aftertwo hours. Both sets of results show that rapamycin elutes at a linearrate over the initial 2 hour period.

The flow elution tests indicate there is a steady release of rapamycinover 7 hours at 37° C. After 24 hours, more than 99% of total drug hadeluted from the stent.

The tests carried out to determine the loading of premounted stentsindicated that on expansion of the stent, drug appeared to flake off thestent surface. Despite this, the loading levels achieved aresubstantially the same as the levels achieved by loading un-mountedstents of the same type.

EXAMPLE 11 Loading Stents Pre-Coated with Cross-Linked Polymer withEtoposide

The stents produced according to Reference Example 1 were loaded withetoposide, an anti-proliferative and anti-neoplastic agent, having amolecular weight of 589 D. It is only slightly soluble in water, thoughis soluble at sufficient levels for stent loading in a 50:50 (volume)mixture or ethanol and water. In this example it is dissolved in such amixed solvent system at a concentration of 15 or 5 g/l and loaded ontothe stent produced in Reference Example 1. For a biodiv Ysio 18 mmlength stent (otherwise coated as described in Reference Example 1, the15 g/l solution produced around 40 mg per stent (loaded from a 2 mlsolution). Full loading appeared to be achieved after 15 minutes, and itproved unnecessary to raise the temperature. Drug elution tests indicatethat a very high proportion of the etoposide is eluted into PBS after 15minutes.

EXAMPLE 12 Loading Stents Precoated with Cross-Linked Polymer withDexamethasone and Dexamethasone Phosphate

Dexamethasone is a corticosteroid, a class of compounds known to bepotent modulators of a range of cellular activities which may haveactivity of inhibiting restenosis. Thus dexamethasone has been shown toreduce reactive intimal hyperplasia in animal models of arterial injury.Systemic delivery of cortico steroids has failed to show a reduction inrestinosis in humans and cortico steroids, administered systemicallyover extended periods of time may have potential adverse side affects.Delivery of dexamethasone from a stent directly to a vessel wall isbelieved to have potential benefit for efficacious performance.Dexamethasone phosphate has a molecular weight of 515.

Biodiv Ysio stents coated using the technique described in ReferenceExample 1, to provide a coating on the interior wall of around 350 nmthickness and on the exterior wall of around 1400 nm thickness, wereloaded with dexamethasone phosphate from solutions in water of 1.0 g/l,2.0 g/l and 5.0 g/l, leading to loadings of, respectively, 9 μg ofdexamethasone phosphate per stent, 14 μg and 20 μg, the loading beingconducted at 20 C. for 30 minutes. Elution tests carried out indicatethat the rate of release of the drug is high, effectively all the drugbeing released within 1 hour, and the half life of the drug releasebeing around 5 minutes.

Similar tests carried out on dexamethasone itself, which has a molecularweight of 390 D and is less water soluble than dexamethasone phosphate,indicates approximately the same level of loading under similarconditions, with a slower rate of release into aqueous medium. Thus thehalf life is around 10 minutes. Around 90% of dexamethasone has beenreleased by around 3 hours.

EXAMPLE 13 Loading Stents Pre-Coated with Cross-Linked Polymer withRoxithromycin

Roxithromycin is a macrolide antibiotic having a molecular weight 840 D.It is prescribed for treatment of a variety of microbial infections inhumans, including chlamydia. Recent research has shown a possible linkbetween chlamydia infections and coronary artery disease in humans.Roxithromycin is substantially insoluble in water, though wholly solublein ethanol. In ethanol/water mixtures, for instance 50:50 mixtures, ahazy solution is formed which is, however, suitable for loading stents.

Stents coated with polymer according to Reference Example 1 (15 mm) wereloaded with roxithromycin from 5 g/l and 10 g/l solutions in ethanol orin ethanol:water 50:50 mixture. The level of loading of drug onto thestent was determined by elution from the stent into ethanol. It wasfound that the higher concentration solutions resulted in higherloadings of roxithromycin, whilst the selection of ethanol orethanol:water made little difference to the loading level. The averageloading for the 5 g/l solution was 58 μg per stent, whilst the 10 g/lsolutions lead to loadings of around 70 μg for both solvent systems.

Stents loaded from the 10 g/l ethanolic solutions were subsequentlycontacted with phosphate buffered saline under gentle agitation and therelease rate determined. The release profile showed that the compoundreleased very slowly, around half the compound having been releasedafter 24 hours. The test was continued up to 48 hours, after which time5 to 10% of roxithromycin remains in the coating.

EXAMPLE 14 Loading Stents Pre-Coated with Cross-Linked Polymer withAspirin

Aspirin has anti platelet activity, which may be useful deliveredlocally from a stent. Aspirin has a molecular weight of 180 D. Aspirinwas dissolved at 10 gm/l or 40 gm/l in ethanol (being only partiallysoluble in water). The solutions were used to load 15 mm stents havingcoatings produced according to Reference Example 1 (interior wallcoating thickness around 350 nanometers, exterior wall coating thicknessaround 1400 nanometers). The stents were immersed in the aspirinsolutions at room temperature for a period of one hour. The stent wasremoved from the solution, excess solution removed by gentle dabbingwith absorbent tissue. Aspirin loading levels were determined byextracting the aspirin into 3 ml ethanol. The results indicated thataround 10 μg aspirin is loaded for the 10 g/l concentration whilstaround 40 μg aspirin is loaded for the 40 g/l solution.

Release of aspirin from the stent into phosphate buffered salineindicated that around 90% of the drug had eluted after about 1 hour.

EXAMPLE 15 Loading Stents Pre-Coated with Cross-Linked Polymer withTetradecylthioacetic Acid

Tetradecylthioacetic acid (TTA) is a compound having a molecular weightof 288 D. It has been identified to have anti-inflammatory properties.It is substantially insoluble in the water. TTA was dissolved in ethanolat concentrations of 10, 25 and 50 g/l and the solutions were conductedwith biodiv Ysio stents (18 mm) coated according to the technique inReference Example 1 below, to have a coating thickness on the interiorwall of around 350 nm and a thickness 1400 nm on the exterior wall. Thestents were immersed in the alcoholic TTA solutions for 30 minutes,removed and allowed to dry in air at ambient temperature for 5 minutes.The loading levels were determined and found to be around 90 μg perstent for the 50 g/l concentration, 30 μg per stent for 25 g/l and 20 μgper stent for the 10 g/l solutions, respectively.

Several stents loaded from the 50 gm/l solution were tested for theirrate of elution into phosphate buffered saline, at 37° C., in a flowsystem as described above in Example 10. The extent of release wasdetermined in the elution tests after periods in the range 1 to 48hours, by extracting residual TTA from the stent into chloroform. Theresults of the elution test are shown in Table 8 below.

TABLE 8 Time point (hours) TTA content per stent (μg/stent) 0 100 1 40 435 8 6 24 2 48 0.2

The loading levels at different concentrations was carried out on 15 mmstents, whilst the elution rates are done 18 mm stents.

The results of the elution tests, shown in FIG. 7, show that initialrelease of TTA is rapid, with release continuing over the period up to48 hours. More than 90% of the drug appears to have been released at 8hours.

EXAMPLE 16 Ex Vivo and In Vivo Tests on Angiopeptin

a) Ex Vivo Tests

More extensive work was conducted on angiopeptin loaded stents, to mimicthe in vivo environment. The further examples use an ex vivo humansaphenous vein model (as described by Armstrong, J. et al 1998. Apurfused organ culture model to investigate drug release from coronarystents, Northern General Hospital, Sheffield (in press). The stents(produced as in Reference Example 1 below) were loaded using aqueoussolutions of angiopeptin labeled with ¹²⁵I by the chloramine T method,into which the stent was dipped for half an hour at 37 C. The loadedstents were then allowed to air dry for one hour. Stents were ininserted into the vein, expanded by balloon catheter, washed in 10 mlculture medium for 10 s then placed in the purpose-built organ culturechamber bathed in 30 ml culture medium. The chamber was then connectedto a circuit and 100 ml culture medium (HEPES-buffered RPMI 1640 culturemedium (LIFE) supplemented with penicillin (100 μl/ml) streptomycin (100units/ml) and glutamine (2 mM)) at 70 ml/min, then removed after 1 houror 24 hours. The stent was subsequently examined to determine theproportion of angiopeptin which has eluted, whilst the vesselimmediately surrounding the stent was investigated to determine theproportion of eluted drug found in the vessel. The culture medium wasalso analysed as was the explanted stent for radio activity.

After 1 hour, 93% of angiopeptin had eluted, of which 13.9% was in thesurrounding vessel concentrated at the stented region. After 24 hours,97% of drug has eluted, of which 7.4% remained in the vesselconcentrated around the stented region. At both times the angiopeptinlevel in the downstream portion of vessel was higher than in theupstream portion. The results indicate that the angiopeptin can bedelivered into human vascular tissue. The released angiopeptinefficiently enters the vessel surrounding the stent. Euluted angiopeptinis found in the culture medium but some may adsorb onto the apparatus.

b) In Vivo Tests

Further work was conducted to investigate the ability of the angiopeptinloaded stents to deliver angiopeptin tissue in an in vivo, in a porcinecoronary artery model. Stents produced as described in Reference Example1 were dipped into aqueous solution of ¹²⁵I-angiopeptin as in stentswere deployed in the coronary artery and then removed after 1 hour, 24hours, 7 days or 28 days. The levels of angiopeptin remaining in thearterial wall immediately surrounding the stent was determined as wellas the level recovered in blood and urine.

After 1 hour, the level of angiopeptin in tissue was around pg/mltissue. After 24 hours, the level of angiopeptin was around 400 pg/ml,whilst at 7 days the level had reduced to around 360 pg/ml. At 28 daysthe level was around 200 pg/ml. After 5 min angiopeptin could beidentified in blood (at 0.08 μg/ml), the level being about the sameafter one hour and reduced to around 0.01 μg/ml after 24 hours. Noangiopeptin could be found in blood at 7 to 28 days. Angiopeptinappeared at 0.29 μg/ml in urine after 1 hour, low levels (0.01 μg/ml)still being detectable in urine after 28 days.

Tissue distribution investigations indicate that at 1 hour, 84% ofreleased angiopeptin is localised in the left anterior descendingcoronary artery. At the longer time points, 1 to 28 days, theangiopeptin is localised to a greater extent in the central section ofLAD surround the stent. At these time points, less than 1% of thedetected angiopeptin is located in tissue other than the heart. After 1hour, 9% of the angiopeptin remained on the stent, after 24 hours 4% ofthe angiopeptin remained and after 7 days, 1.5% of the angiopeptinremained on the stent.

Conclusion

Extrapolation of these results for angiopeptin to other drugs, comparingin vitro elution rates ex vivo and in vivo, allow a prediction that therelease of drug will be extremely localised to surrounding tissue,rather than to the circulation. Furthermore the drug will be retained atthe delivery site over extended periods of time. It appears thatangiopeptin is eluted very quickly into the system initially, presumablyby elution from the lumenal (interior wall) surface of the stent.

EXAMPLE 17 Coating Stents with Etoposide/Polymer Premixes

In this example, rather than precoating the polymer according toreference Example 1, followed by loading of drug, a premix of drug andcrosslinkable polymer is formed and coated onto a stent. Thecrosslinkable polymer is identical to that used in Reference Example 1,0.932 g polymer being dissolved into a 1:1 ethanol:water (by volume)mixture (50 ml). 0.06 g etoposide was dissolved into the solution andthe mixed coating solution coated onto a stent using the same techniqueas in Reference Example 1, to produce a thicker coating on the outsideas compared to the inside. The coated stents were cured overnight at atemperature in the range 50 to 70 C.

The amount of drug loaded into the stents was determined by elution intoan ethanol:water 50:50 (volume) mixture. The results indicated anaverage etoposide loading of around 12 μg per stent. If it is assumedthat the weight of mixed coating is the same as the weight achieved bythe technique of reference Example 1 would lead to a prediction thataround 9 to 13 μg per stent of etoposide would be expected to bedeposited. The amount of etoposide eluted into ethanol:water is in thisrange. This is believed to indicate that crosslinking of the polymer inthe presence of drug does not change the drug chemically, nor inhibitfull elution.

Stents produced by the above technique were also tested to determine therate of release of etoposide into 5 ml phosphate buffered saline,indicated that the initial rate of release was fast and plateaued ataround 5 minutes, this being presumed to represent substantially fullrelease. The release rate, from the results, for the stent coated with apolymer crosslinked in the presence of drug indicate that the release ofdrug may not be slowed down as compared to the alternative system, whereprecoated stents are contacted with a solution of drug.

EXAMPLE 18 Ex Vivo Tests on Polymer/Dipyridamole Coated Stents

Palmaz-Schatz Stents (trade mark) were coated with a solution of thesame polymer as used in Reference Example 1, dissolved in ethanol at 50g/l concentration, also containing dipyridamole at 30 g/l concentration.Stents were dipped into the solution by hand, using several coatingsteps. The stents were then cured overnight at 70 C. in moist air.

The coated stents were tested in an ex vivo model using fresh humansaphenous vein, previously washed in the same culture medium as is usedin Example 16 above, in the ex vivo tests. The stents were deliveredinto veins, which were subsequently deposited into apparatus used inExample 16. The circulating liquid, and the vessel wall were analysed at1, 6 or 24 hours to determine localisation of dipyridamole. Dipyridamolecan be detected in the circulating medium after one hour, the levelincreasing over the twenty four hour test period. Similarly, the levelof dipyridamole remaining on the stent decreases from 1 hour to 24hours. Using the detection techniques, no dipyridamole could be seenwithin the vessel wall until twenty four hours after stent deployment.At this time, dipyridamole is concentrated in the section of the veinimmediately surrounding the stent with lower levels in the vesselimmediately adjacent those sections.

These results indicate that drug is released from a coating which hasbeen crosslinked in the presence of the drug.

REFERENCE EXAMPLE 1 Asymmetric Coating of Stents with Cross-LinkableZwitterionic Polymer

In this example, the production of polymer coated stents having athicker coating on the outer surface, is described. 15 mm (length)biodiv Ysio stents, formed of 316L stainless steel are coated withsolutions of a crosslinkable polymer formed from2-methacryloxy-2′-trimethylamoniumethylphosphate inner salt (23 parts bymole), dodecylmethacrylate (47 parts by mole),3-hydroxypropylmthacrylate (25 parts by mole) and3-trimethoxysilylpropylmethacrylate (5 parts by mole) in ethanol. Thequater polymer was synthesised as described in WO-A-9830615. The stentswere coated using the apparatus described in WO-A-0004999, followed bycuring overnight by maintaining the stents at a temperature of in therange 50-70° C. The thickness of the coating on the struts on theinterior and exterior surfaces was determined using an atomic forcemicroscope. The conditions were varied, by changing one or more of thefollowing features: polymer concentration (between 10 and 50 g/l), thespeed at which the stent is dipped into and removed from the coatingsolution, the pressure difference between the perforated needlepositioned in the lumen of the stent and the space outside the stentwall, the number of coating steps and the period for which each coatingis allowed to dry between coating steps. The effect of the changes onthe thickness of the coating on the interior and exterior surfaces ofthe struts, as well as the avoidance of bridging or webbing between thestruts was optimised. The conditions were selected so as to achieve anaverage coating thickness on the internal wall of around 350 nm, and anaverage thickness on the external wall of around 1400 nm.

In the optimisation tests, the conditions tested allowed the ratio ofthe thickness of the interior and exterior walls to be varied in therange 1:(1.5 to 10). The coating on the interior wall was varied betweenabout 40 and about 900 nm. The thickness on the exterior wall was variedbetween about 400 and about 1500 nm.

These stents were used in drug delivery tests of the above Examples.

REFERENCE EXAMPLE 2 Asymmetric Coating of Stents with Other Polymers

Using the same general coating technique as described for ReferenceExample 1, biodivysio stents were coated using solutions of differentpolymers in appropriate solvent systems. In each case the polymerconcentration was 2% weight/volume. The following polymer:solventcombinations were used:

polyethyleneglycol (10,000 D average molecular weight) in ethanol:water(1:1 volume)

poly(DL-lactide-co-glycolide) in chloroform

nylon 6/6 (poly(hexamethylene adipamide) in trifluoroethanol

Tecoflex (trade mark) (polyurethane) in tetrahydrofuran

poly(3-hydroxybutyric acid-co-3-hydroxyvaleric acid) (5% PHV) inchloroform

poly(acrylic acid) in ethanol:water (1:0.06 volume).

The coated stents were dried in an appropriate manner. After coating theaverage thickness on the interior and exterior wall surfaces weredetermined using atomic force microscopy. The results indicated that,whilst the actual thicknesses differed between the various polymers, allformed asymmetric coating thickness, with thicker coatings on theexterior wall surface. The ratio of thickness between inside and outsidewas 1:(2 to 6). The polyethyleneglycol produced the lowest exterior wallthickness at 420 nm, whilst the polyacrylic acid formed the thickestexterior surface at 2.3 μm.

The asymmetric coated stents could be used in the novel process in whichthe coating is swollen by contact with a drug-containing solution in asuitable solvent, or by coating the stent with a mixed solution ofpolymer and drug.

1. A process for producing an implant, for immediate implant into a patient, that is loaded with a pharmaceutically active agent comprising the steps: a) providing a sterile coated implant comprising a biostable implant and a coating comprising a polymer matrix which has pendant zwitterionic groups; b) providing a pharmaceutical solution comprising a pharmaceutically active agent in solution in a solvent which is capable of swelling the coating; c) contacting the coated implant with the pharmaceutical solution at a temperature and for a time to allow swelling of the coating to an extent in the range 25 to 95% of the equilibrium swelling at 37° C. in the pharmaceutical solution; and d) drying the treated implant by solvent evaporation to remove 10 to 100% of total solvent, to produce a pharmaceutically active loaded implant, wherein providing the sterile coated implant comprises: a1) coating a biostable implant with a coating composition containing the polymer of the matrix, or a precursor thereof, a2) curing the polymer to form the said polymer matrix; and a3) sterilising the implant coated with the polymer matrix.
 2. A process according to claim 1 in which the polymer matrix is substantially non-biodegradable.
 3. A process according to claim 2 in which the polymer matrix is covalently crosslinked and/or bound to the implant surface.
 4. A process according to claim 2 in which the coating composition contains a cross-linkable polymer and in which curing involves cross-linking the polymer.
 5. A process according to claim 2 in which the polymer in the coating composition is formed from ethylenically unsaturated monomers including a zwitterionic monomer.
 6. A process according to claim 5 in which the ethylenically unsaturated monomers include a surface binding monomer, selected from a hydrophobic comonomer, a reactive monomer having one or more pendant reactive groups capable of forming intermolecular cross-links, and mixtures thereof.
 7. A process according to claim 5 in which the zwitterionic monomer has the general formula I: YBX  I wherein B is selected from the group consisting of straight and branched alkylene, alkylene-oxaalkylene and alkylene oligo-oxaalkylene chains optionally containing one or more fluorine atoms up to and including perfluorinated chains and, if X or Y contains a terminal carbon atom bonded to B, a valence bond; X is a zwitterionic group; and Y is an ethylenically unsaturated polymerisable group selected from the group consisting of

CH₂═C(R)CH₂O—, CH₂═C(R)CH₂OC(O)—, CH₂═C(R)OC(O)—, CH₂═C(R)O—, CH₂═C(R)CH₂OC(O)N(R¹)—, R²OOCCR═CRC(O)O—, RCH═CHC(O)O—, RCH═C(COOR²)CH₂C(O)O—,

wherein: R is hydrogen or a C₁-C₄ alkyl group; R¹ is hydrogen or a C₁-C₄ alkyl group or R¹ is —B—X where B and X are as defined above; and R² is hydrogen or a C₁₋₄ alkyl group; A is —O— or —NR¹—; K is selected from the group consisting of —(CH₂)_(p)OC(O)—, —(CH₂)_(p)C(O)O—, —(CH₂)_(p)OC(O)O—, —(CH₂)_(p)NR³—, —(CH₂)_(p)NR³C(O)—, —(CH₂)_(p)C(O)NR³—, —(CH₂)_(p)NR³C(O)O—, —(CH₂)_(p)OC(O)NR³—, —(CH₂)_(p)NR³C(O)NR³— (in which the groups R³ are the same or different), —(CH₂)_(p)O—, —(CH₂)_(p)SO₃—, and, optionally in combination with B, a valence bond p is from 1 to 12; and R³ is hydrogen or a C₁-C₄ alkyl group.
 8. A process according to claim 7 in which X is a group of the general formula V

in which X³ and X⁴, which are the same or different, are selected from the group consisting of —O—, —S—, —NH— and a valence bond, and W⁺ is selected from the group consisting of —W¹—N⁺R¹¹ ₃, —W¹—P⁺R¹¹ ₃, —W¹—S⁺R¹¹ ₂ or —W¹⁻Het⁺ in which: W¹ is selected from the group consisting of alkanediyl of 1-6 carbon atoms optionally containing one or more ethylenically unsaturated double or triple bonds, disubstituted-aryl, alkylene aryl, aryl alkylene, alkylene aryl alkylene, disubstituted cycloalkyl, alkylene cycloalkyl, cycloalkyl alkylene and alkylene cycloalkyl alkylene, which group W¹ optionally contains one or more fluorine substituents and/or one or more functional groups; and either the groups R¹⁰ are the same or different and each is selected from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms and aryl, or two of the groups R¹⁰ together with the nitrogen atom to which they are attached form a heterocyclic ring containing from 5 to 7 atoms or the three groups R¹⁰ together with the nitrogen atom to which they are attached form a fused ring structure containing from 5 to 7 atoms in each ring, and optionally one or more of the groups R¹⁰ is substituted by a hydrophilic functional group, and the groups R¹¹ are the same or different and each is R¹⁰ or a group OR¹⁰, where R¹⁰ is as defined above; and Het is selected from the group consisting of aromatic nitrogen-, phosphorus- and sulphur-containing rings.
 9. A process according to claim 8 in which X is a group of formula VI:

where the groups R¹² are the same or different and each is hydrogen or C₁₋₄ alkyl, and e is from 1 to
 4. 10. A process according to claim 9 in which each group R¹² is methyl, and in which e is 2 or
 3. 11. A process according to claim 5 in which the surface binding monomer has the general formula VII Y¹R¹³  VII wherein Y¹ is selected from the group consisting of

CH₂═C(R¹⁴)CH₂O—, CH₂═C(R¹⁴)CH₂OC(O)—, CH₂═C(R¹⁴)OC(O)—, CH₂═C(R¹⁴)O—, CH₂═C(R¹⁴)CH₂OC(O)N(R¹⁵)—, R¹⁶OOCCR¹⁴═CR¹⁴C(O)O—, R¹⁴CH═CHC(O)O—, R¹⁴CH═C(COOR¹⁶)CH₂C(O)—O—,

wherein: R¹⁴ is hydrogen or a C₁-C₄ alkyl group; R¹⁵ is hydrogen or a C₁-C₄ alkyl group or R¹⁵ is R¹³; R¹⁶ is hydrogen or a C₁₋₄ alkyl group; A¹ is —O— or —NR¹⁵—; and K¹ is selected from the group consisting of —(CH₂)_(q)OC(O)—, —(CH₂)_(q)C(O)O—, (CH₂)_(q)OC(O)O—, —(CH₂)_(q)NR¹⁷—, —(CH₂)_(q)NR¹⁷C(O)—, —(CH₂)_(q)C(O)NR¹⁷—, —(CH₂)_(q)NR¹⁷C(O)O—, —(CH²)_(q)OC(O)NR¹⁷—, —(CH₂)_(q)NR¹⁷C(O)NR¹⁷— (in which the groups R¹⁷ are the same or different), —(CH₂)_(q)O—, —(CH₂)_(q)SO₃—, and a valence bond q is from 1 to 12; and R¹⁷ is hydrogen or a C₁-C₄ alkyl group; and R¹³ is a surface binding group, selected from hydrophobic groups and ionic groups.
 12. A process according to claim 11 in which R¹³ is a straight chain alkyl having 8 to 18 carbon atoms.
 13. A process according to claim 5 in which the reactive monomer has the general formula VIII Y²B²R²⁰  VIII wherein B² is selected from the group consisting of straight or branched alkylene, oxaalkylene and oligo-oxaalkylene chain optionally containing one or more fluorine atoms up to and including perfluorinated chains, and a valence bond; Y² is an ethylenically unsaturated polymerisable group selected from the group consisting of

CH₂═C(R²¹)CH₂—O—, CH₂═C(R²¹)CH₂OC(O)—, CH₂═C(R²¹)OC(O)—, CH₂═C(R²¹)O—, CH₂═C(R²¹)CH₂OC(O)N(R²²)—, R²³OOCCR²¹═CR²¹C(O)O—, R²¹H═CHC(O)O—, R²¹H═C(COOR²³)CH₂C(O)O—

where R²¹ is hydrogen or C₁-C₄ alkyl; R²³ is hydrogen, or a C₁₋₄-alkyl group; A² is —O— or —NR²²—; R²² is hydrogen or a C₁-C₄ alkyl group or R²² is a group B²R²⁰; K² is selected from the group consisting of —(CH₂)_(k)OC(O)—, —(CH)_(k)C(O)O—, —(CH₂)_(k)OC(O)O—, —(CH₂)_(k)NR²²—, —(CH₂)_(k)NR²²C(O)—, —(CH₂)_(k)OC(O)O—, —(CH₂)_(k)NR²²—, —(CH₂)_(k)NR²²C(O)—, —(CH₂)_(k)C(O)NR²²—, —(CH₂)_(k)NR²²C(O)O—, —(CH₂)_(k)OC(O)NR²²—, —(CH₂)_(k)NR²²C(O)NR²²— (in which the groups R²² are the same or different), —(CH₂)_(k)O—, —(CH₂)_(k)SO₃—, and a valence bond and k is from 1 to 12; and R²⁰ is a cross-linkable group.
 14. A process according to claim 13 in which R²⁰ is selected from the group consisting of ethylenically and acetylenically unsaturated groups containing radicals; aldehyde groups; silane and siloxane groups containing one or more substituents selected from halogen atoms and C₁₋₄ alkoxy groups; hydroxyl; amino; carboxyl; epoxy; —CHOHCH₂Hal (in which Hal is selected from chlorine, bromine and iodine atoms); succinimido; tosylate; triflate; imidazole carbonyl amino; optionally substituted triazine groups, acetoxy; mesylate; carbonyl di(cyclo)alkyl carbodiimidoyl; isocyanate, acetoacetoxy; and oximino.
 15. A process according to claim 14 in which R²⁰ comprises a silane group containing at least one substituent selected from halogen atoms and C₁₋₄-alkoxy groups.
 16. A process according to claim 15 in which R²⁰ is a trimethoxysilyl group.
 17. A process according to claim 1 in which the thickness of the coating of polymer matrix of the sterile coated implant is in the range 500 nm to 500 μm.
 18. A process according to claim 1 in which step c) is conducted at about 37° C.
 19. A process according to claim 1 in which step c) is conducted over a period in the range 1 min to 30 min.
 20. A process according to claim 1 in which the implant is a stent, a stent-graft or a vascular graft.
 21. A process according to claim 20 in which the implant is a vascular stent.
 22. A process according to claim 21 in which both inner and outer surfaces of the stent are coated with polymer matrix and both polymer coated surfaces are contacted with pharmaceutical solution in step c).
 23. A process according to claim 22 in which the ratio of thickness of polymer matrix on the outer to the inner surface is (at least 1.5):1.
 24. A process according to claim 1 in which the pharmaceutically active agent is selected from the group consisting of dipyridamole, angiopeptin, taxol, roxithromycin, rapamycin, tetradecylthioacetic acid, aspirin, etoposide and dexamethasone.
 25. A process for producing an implant loaded with a pharmaceutically active agent comprising the steps: i) providing an implant selected from a graft, a stent and a stent-graft having a polymer matrix coating on its inner and outer surfaces, the said polymer of the matrix being a cross-linked polymer formed from ethylenically unsaturated monomer including a) a zwitterionic monomer of the general formula I YBX  I wherein B is selected from the group consisting of straight and branched alkylene, alkylene-oxaalkylene and alkylene oligo-oxaalkylene chain optionally containing one or more fluorine atoms up to and including perfluorinated chains and, if X or Y contains a terminal carbon atom bonded to B, a valence bond; X is a zwitterionic group; and Y is an ethylenically unsaturated polymerisable group selected from the group consisting of

CH₂═C(R)CH₂O—, CH₂═C(R)CH₂OC(O)—, CH₂═C(R)OC(O)—, CH₂═C(R)O—, CH₂═C(R)CH₂OC(O)N(R¹)—, R²OOCCR═CRC(O)O—, RCH═CHC(O)O—, RCH═C(COOR²)CH₂C(O)O—,

wherein: R is hydrogen or a C₁-C₄ alkyl group; R¹ is hydrogen or a C₁-C₄ alkyl group or R¹ is —B—X where B and X are as defined above; and R² is hydrogen or a C₁₋₄ alkyl group; A is —O— or —NR¹—; K is selected from the group consisting of —(CH₂)_(p)OC(O)—, —(CH₂)_(p)C(O)O—, —(CH₂)_(p)OC(O)O—, —(CH₂)_(p)NR³—, —(CH₂)_(p)NR³C(O)—, —(CH₂)_(p)C(O)NR³—, —(CH₂)_(p)NR³C(O)O—, —(CH₂)_(p)OC(O)NR³—, —(CH₂)_(p)NR³C(O)NR³— (in which the groups R³ are the same or different), —(CH₂)_(p)O—, —(CH₂)_(p)SO₃—, and, optionally in combination with B, a valence bond p is from 1 to 12; and R³ is hydrogen or a C₁-C₄ alkyl group; b) a surface binding monomer of the general formula VII Y¹R¹³  VII wherein Y¹ is selected from the group consisting of

CH₂═C(R¹⁴)CH₂O—, CH₂═C(R¹⁴)CH₂OC(O)—, CH₂═C(R¹⁴)OC(O)—, CH₂═C(R¹⁴)O—, CH₂═C(R¹⁴)CH₂OC(O)N(R¹⁵)—, R¹⁶OOCCR¹⁴═CR¹⁴C(O)O—, R¹⁴CH═CHC(O)O—, R¹⁴CH═C(COOR¹⁶)CH₂C(O)—)—,

wherein: R¹⁴ is hydrogen or a C₁-C₄ alkyl group; R¹⁵ is hydrogen or a C₁-C₄ alkyl group or R¹⁵ is R¹³; R¹⁶ is hydrogen or a C₁₋₄ alkyl group; A¹ is —O— or —NR¹⁵—, and K¹ is selected from the group consisting of —(CH₂)_(q)OC(O)—, —(CH₂)_(q)C(O)O—, (CH₂)_(q)OC(O)O—, —(CH₂)_(q)NR¹⁷—, —(CH₂)_(q)NR¹⁷C(O)—, —(CH₂)_(q)C(O)NR¹⁷—, —(CH₂)_(q)NR¹⁷(O)O—, —(CH₂)_(q)OC(O)NR¹⁷—, —(CH₂)_(q)NR¹⁷(O)NR¹⁷— (in which the groups R¹⁷ are the same or different), —(CH₂)_(q)O—, —(CH₂)_(q)SO₃—, and a valence bond q is from 1 to 12; and R¹⁷ is hydrogen or a C₁-C₄ alkyl group; and R¹³ is a surface binding group, selected from hydrophobic groups and ionic groups; and c) a reactive monomer of the general formula VIII Y²B²R²⁰  VIII wherein B² is selected from the group consisting of straight and branched alkylene, oxaalkylene and oligo-oxaalkylene chain optionally containing one or more fluorine atoms up to and including perfluorinated chains, and a valence bond; Y² is an ethylenically unsaturated polymerisable group selected from the group consisting of

CH₂═C(R²¹)CH₂—O—, CH₂═C(R²¹)CH₂OC(O)—, CH₂═C(R²¹)OC(O)—, CH₂═C(R²¹)O—, CH₂═C(R²¹)CH₂OC(O)N(R²²)—, R²³OOCCR²¹═CR²¹C(O)O—, R²¹H═CHC(O)O—, R²¹H═C(COOR²³)CH₂C(O)O—

where R²¹ is hydrogen or C₁-C₄ alkyl; R²³ is hydrogen, or a C₁₋₄-alkyl group; A² is —O— or —NR²²—; R²² is hydrogen or a C₁-C₄ alkyl group or R²² is a group B²R²⁰; K² is selected from the group consisting of —(CH₂)_(k)OC(O)—, —(CH)_(k)C(O)O—, —(CH₂)_(k)OC(O)O—, —(CH₂)_(k)NR²²—, —(CH₂)_(k)NR²²C(O)—, —(CH₂)_(k)OC(O)O—, —(CH₂)_(k)NR²²—, —(CH₂)_(k)NR²²C(O)—, —(CH₂)_(k)C(O)NR²²—, —(CH₂)_(k)NR²²C(O)O—, —(CH₂)_(k)OC(O)NR²²—, —(CH₂)_(k)NR²²C(O)NR²²— (in which the groups R²² are the same or different), —(CH₂)_(k)O—, —(CH₂)_(k)SO₃—, and a valence bond and k is from 1 to 12; and R²⁰ is a silyl group having three alkoxy substituents; and the thickness of the coating being in the range of 500 nm to 500 μm, wherein the outer surface of the stent is provided with a thicker coating of cross-linkable polymer than the inner surface wherein the ratio of the thickness of the coating on the outer surface to the inner surface is in the range of (at least 1.5):1; ii) providing a pharmaceutical solution comprising a pharmaceutically active agent having a molecular weight of up to 1200 D in solution in a solvent which is capable of swelling the coating; iii) contacting the coated implant with the pharmaceutical solution; and iv) drying the treated implant by solvent evaporation to remove 10 to 100% of total solvent, to produce a pharmaceutically active loaded implant.
 26. A process according to claim 25 in which X is a group of formula VI:

where the groups R¹² are the same or different and each is hydrogen or C₁₋₄ alkyl, and e is from 1 to
 4. 27. A process according to claim 26 in which B is C₂₋₆ alkanediyl and Y is H₂C═CRCOA- in which R is H or CH₃ and A is O or NH.
 28. A process according to claim 25 in which R¹³ is a straight chain alkyl having 8 to 18 carbon atoms.
 29. A process according to claim 28 in which Y¹ is H₂C═CR¹⁴COA¹- in which R¹⁴ is H or CH₃ and A¹ is O or NH.
 30. A process according to claim 25 in which R²⁰ is trimethoxysilyl, B² is C₂₋₆ alkanediyl and Y² is H₂C═CR²¹COA² in which R²¹ is H or CH₃ and A² is O or NH.
 31. A process according to claim 25 in which X is a group of formula VI:

where the groups R¹² are the same or different and each is hydrogen or C₁₋₄ alkyl, and e is from 1 to 4; B is C₂₋₆ alkanediyl; Y is H₂C═CRCOA- in which R is H or CH₃ and A is O or NH; R¹³ is a straight chain alkyl having 8 to 18 carbon atoms; Y¹ is H₂C—CR¹⁴COA¹ in which R¹⁴ is H or CH₃ and A¹ is O or NH; R²⁰ is trimethoxysilyl, B² is C₂₋₆ alkanediyl; and Y² is H₂C—CR²¹COA²- in which R²¹ is H or CH₃ and A² is O or NH.
 32. A process according to claim 25 in which the thickness of the coating of polymer matrix of the sterile coated implant is in the range of 500 nm to 500 μm.
 33. A process according to claim 25 in which step i) comprises the steps: ia) providing a coating composition comprising cross-linkable polymer formed from ethylenically unsaturated monomers including said zwitterionic monomer, said surface binding monomer and said ractive monomer; ib) coating the implant with the coating composition whereby an implant is coated with cross-linkable polymer; and ic) curing the cross-linkable polymer under conditions such that the trialkoxy silyl group R²⁰ form inter molecular cross-links to form a crosslinked polymer matrix coating.
 34. A process according to claim 33 in which the implant is a vascular stent, having inner and outer surfaces.
 35. A process according to claim 34 in which the outer surface of the stent is provided with a thicker coating of cross-linkable polymer than the inner surface in step ib).
 36. A process for providing a pharmaceutical-loaded stent comprising the steps: a) providing a stent comprising a generally tubular body formed of substantially impermeable biostable material and having interior and exterior surfaces; b) providing the interior and exterior surfaces of the stent with a coating of cross-linkable polymer in such a manner that the outer surface of the stent is provided with a thicker coating of cross-linkable polymer than the inner surface, the ratio of the thickness of the coatings on the exterior and interior surfaces being (1.5-50):1 and the thickness of the biocompatible coating on the exterior surface is in the range 500 nm to 500 μm; c) cross-linking the cross-linkable polymer to provide a cross-linked biostable polymer matrix coated stent; d) sterilising the coated stent; e) providing a pharmaceutical solution comprising a pharmaceutical active having molecular weight up to 1200 D in solution in a solvent which is capable of swelling the cross-linked polymer matrix of the sterilised stent coating; f) contacting the coated sterilised stent with the pharmaceutical solution by dipping for a period in the range 30 seconds to 30 minutes, whereby the polymer matrix swells and pharmaceutical active is dispersed through the matrix to produce a pharmaceutical active loaded implant wherein the cross-linkable polymer is formed from ethylenically unsaturated monomers including a zwitterionic monomer and a reactive monomer; wherein the said cross-linking involves reaction of the reactive monomer residues to form inter molecular cross-links; and wherein the cross-linked polymer is water-swellable and biocompatible.
 37. A process according to claim 36 in which the thickness of the biocompatible coating on the exterior surface is in the range 500 nm to 5 μm.
 38. A process according to claim 36 in which the solvent is selected from the group consisting of alcohols, glycols, water and mixtures thereof.
 39. A process according to claim 38 in which the solvent comprises an alcohol which is a lower alkanol.
 40. A process according to claim 36 in which the ethylenically unsaturated monomers include a surface binding monomer, selected from a hydrophobic comonomer, a reactive monomer having one or more pendant reactive groups capable of forming intermolecular cross-links, and mixtures thereof.
 41. A process according to claim 36 in which the zwitterionic monomer has the general formula I: YBX  I wherein B is selected from the group consisting of straight and branched alkylene, alkyleneoxaalkylene and alkylene oligo-oxaalkylene chains optionally containing one or more fluorine atoms up to and including perfluorinated chains and, if X or Y contains a terminal carbon atom bonded to B, a valence bond; X is a zwitterionic group; and Y is an ethylenically unsaturated polymerisable group selected from the group consisting of

CH₂═C(R)CH₂O—, CH₂═C(R)CH₂OC(O)—, CH₂═C(R)OC(O)—, CH₂═C(R)O—, CH₂═C(R)CH₂OC(O)N(R¹)—, R²OOCCR═CRC(O)O—, RCH═CHC(O)O—, RCH═C(COOR²)CH₂C(O)O—,

wherein: R is hydrogen or a C₁-C₄ alkyl group; R¹ is hydrogen or a C₁-C₄ alkyl group or R¹ is —B—X where B and X are as defined above; and R² is hydrogen or a C₁₋₄ alkyl group; A is —O— or —NR¹—; K is selected from the group consisting of —(CH₂)_(p)OC(O)—, —(CH₂)_(p)C(O)O—, —(CH₂)_(p)OC(O)O—, —(CH₂)_(p)NR³—, —(CH₂)_(p)NR³C(O)—, —(CH₂)_(p)C(O)NR³—, —(CH₂)_(p)NR³C(O)O—, —(CH₂)_(p)OC(O)NR³—, —(CH₂)_(p)NR³C(O)NR³— (in which the groups R³ are the same or different), —(CH₂)_(p)O—, —(CH₂)_(p)SO₃—, and, optionally in combination with B, a valence bond p is from 1 to 12; and R³ is hydrogen or a C₁-C₄ alkyl group.
 42. A process according to claim 41 in which X is a group of formula VI:

where the groups R¹² are the same or different and each is hydrogen or C₁₋₄ alkyl, and e is from 1 to
 4. 43. A process according to claim 42 in which B is C₂₋₆ alkanediyl and Y is H₂C═CRCOA in which R is H or CH₃ and A is O or NH.
 44. A process according to claim 40 in which the surface binding monomer has the general formula VII Y¹R¹³  VII wherein Y¹ is selected from the group consisting of

CH₂═C(R¹⁴)CH₂O—, CH₂═C(R¹⁴)CH₂OC(O)—, CH₂═C(R¹⁴)OC(O)—, CH₂═C(R¹⁴)O—, CH₂═C(R¹⁴)CH₂OC(O)N(R¹⁵)—, R¹⁶OOCCR¹⁴═CR¹⁴C(O)O—, R¹⁴CH═CHC(O)O—, R¹⁴CH═C(COOR¹⁶)CH₂C(O)—)—,

wherein: R¹⁴ is hydrogen or a C₁-C₄ alkyl group; R¹⁵ is hydrogen or a C₁-C₄ alkyl group or R¹⁵ is R¹³; R¹⁶ is hydrogen or a C₁₋₄ alkyl group; A¹ is —O— or —NR¹⁵—; and K¹ is selected from the group consisting of —(CH₂)_(q)OC(O)—, —(CH₂)_(q)C(O)O—, (CH₂)_(q)OC(O)O—, —(CH₂)_(q)NR¹⁷—, —(CH₂)_(q)NR¹⁷C(O)—, —(CH₂)_(q)C(O)NR¹⁷—, —(CH₂)_(q)NR¹⁷C(O)O—, —(CH₂)_(q)OC(O)NR¹⁷—, —(CH₂)_(q)NR¹⁷C(O)NR¹⁷— (in which the groups R¹⁷ are the same or different), —(CH₂)_(q)O—, —(CH₂)_(q)SO₃—, and a valence bond q is from 1 to 12; and R¹⁷ is hydrogen or a C₁-C₄ alkyl group; and R¹³ is a surface binding group, selected from hydrophobic groups and ionic groups.
 45. A process according to claim 44 in which R¹³ is a straight chain alkyl having 8 to 18 carbon atoms.
 46. A process according to claim 45 in which Y¹ is H₂C═CR¹⁴COA¹ in which R¹⁴ is H or CH₃ and A¹ is O or NH.
 47. A process according to claim 40 in which the reactive monomer has the general formula VIII Y²B²R²⁰  VIII wherein B² is selected from the group consisting of straight or branched alkylene, oxaalkylene and oligo-oxaalkylene chain optionally containing one or more fluorine atoms up to and including perfluorinated chains, and a valence bond; Y² is an ethylenically unsaturated polymerisable group selected from the group consisting of

CH₂═C(R²¹)CH₂—O—, CH₂═C(R²¹)CH₂OC(O)—, CH₂═C(R²¹)OC(O)—, CH₂═C(R₂₁)O—, CH₂═C(R²¹)CH₂OC(O)N(R²²)—, R²³OOCCR²¹═CR²¹C(O)O—, R²¹H═CHC(O)O—, R²¹H═C(COOR²³)CH₂C(O)O—

where R²¹ is hydrogen or C₁-C₄ alkyl; R²³ is hydrogen, or a C₁₋₄ alkyl group; A² is —O— or —NR²²—; R²² is hydrogen or a C₁-C₄ alkyl group or R²² is a group B²R²⁰; K² is selected from the group consisting of —(CH₂)_(k)OC(O)—, —(CH)_(k)C(O)O—, —(CH₂)_(k)OC(O)O—, —(CH₂)_(k)NR²²—, —(CH₂)_(k)NR²²C(O)—, —(CH₂)_(k)OC(O)O—, —(CH₂)_(k)NR²²—, —(CH₂)_(k)NR²²C(O)—, —(CH₂)_(k)C(O)NR²²—, —(CH₂)_(k)NR²²C(O)O—, —(CH₂)_(k)OC(O)NR²²—, —(CH₂)_(k)NR²²C(O)NR²²— (in which the groups R²² are the same or different), —(CH₂)_(k)O—, —(CH₂)_(k)SO₃—, and a valence bond and k is from 1 to 12; and R²⁰ is a cross-linkable group.
 48. A process according to claim 47 in which R²⁰ is selected from the group consisting of ethylenically and acetylenically unsaturated groups containing radicals; aldehyde groups; silane and siloxane groups containing one or more substituents selected from halogen atoms and C₁₋₄ alkoxy groups; hydroxyl; amino; carboxyl; epoxy; —CHOHCH₂Hal (in which Hal is selected from chlorine, bromine and iodine atoms); succinimido; tosylate; triflate; imidazole carbonyl amino; optionally substituted triazine groups; acetoxy; mesylate; carbonyl di(cyclo)alkyl carbodiimidoyl; isocyanate, acetoacetoxy; and oximino.
 49. A process according to claim 48 in which R²⁰ comprises a silane group containing at least one substituent selected from halogen atoms and C₁₋₄ alkoxy groups.
 50. A process according to claim 49 in which R²⁰ is trimethoxysilyl, B² is C₂₋₆ alkanediyl and Y² is H₂C═CR²¹COA²- in which R²¹ is H or CH₃ and A² is O or NH.
 51. A process according to claim 36 wherein each biocompatible coating is 500 nm to 5 μm thick.
 52. A process for producing an implant loaded with a pharmaceutically active agent comprising the steps: a) providing a sterile coated implant comprising a biostable implant and a coating comprising a polymer matrix that is covalently cross-linked and/or bound to the implant surface and has pendant zwitterionic groups, wherein the polymer matrix is formed from cross-linked polymer formed from ethylenically unsaturated monomers consisting of a zwitterionic monomer, a surface binding monomer, and optional reactive monomer and diluent comonomer, wherein the zwitterionic monomer has the general formula I: YBX  I wherein B is selected from the group consisting of straight and branched alkylene, alkylene-oxaalkylene and alkylene oligo-oxaalkylene chains optionally containing one or more fluorine atoms up to and including perfluorinated chains and, if X or Y contains a terminal carbon atom bonded to B, a valence bond; X is a zwitterionic group of the general formula V

in which X³ and X⁴, which are the same or different, are selected from the group consisting of —O—, —S—, —NH— and a valence bond, and W⁺ is selected from the group consisting of —W¹—N⁺R¹¹ ₃, —W¹—P⁺R¹¹ ₃, —W¹—S⁺R¹¹ ₂ or —W¹-Het⁺ in which: W¹ is selected from the group consisting of alkanediyl of 1-6 carbon atoms optionally containing one or more ethylenically unsaturated double or triple bonds, disubstituted-aryl, alkylene aryl, aryl alkylene, alkylene aryl alkylene, disubstituted cycloalkyl, alkylene cycloalkyl, cycloalkyl alkylene and alkylene cycloalkyl alkylene, which group W¹ optionally contains one or more fluorine substituents and/or one or more functional groups; and either groups R¹⁰ are the same or different and each is selected from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms and aryl, or two of the groups R¹⁰ together with the nitrogen atom to which they are attached form a heterocyclic ring containing from 5 to 7 atoms or three groups R¹⁰ together with the nitrogen atom to which they are attached form a fused ring structure containing from 5 to 7 atoms in each ring, and optionally one or more of the groups R¹⁰ is substituted by a hydrophilic functional group, and the groups R¹¹ are the same or different and each is R¹⁰ or a group OR¹⁰, where R¹⁰ is as defined above; and Het is selected from the group consisting of aromatic nitrogen-, phosphorus- and sulphur-containing rings; and Y is an ethylenically unsaturated polymerisable group selected from the group consisting of

CH₂═C(R)CH₂O—, CH₂═C(R)CH₂OC(O)—, CH₂═C(R)OC(O)—, CH₂═C(R)O—, CH₂═C(R)CH₂OC(O)N(R¹)—, R²OOCCR═CRC(O)O—, RCH═CHC(O)O—, RCH═C(COOR²)CH₂C(O)O—,

wherein R is hydrogen or a C₁-C₄ alkyl group; R¹ is hydrogen or a C₁-C₄ alkyl group or R¹ is —B—X where B and X are as defined above; and R² is hydrogen or a C₁₋₄ alkyl group; A is —O— or NR¹—; K is selected from the group consisting of —(CH₂)_(p)OC(O)—, —(CH₂)_(p)C(O)O—, —(CH₂)_(p)OC(O)O—, —(CH₂)_(p)NR³, —(CH₂)_(p)NR³C(O)—, —(CH₂)_(p)C(O)NR³—, —(CH₂)_(p)NR³C(O)O—, —(CH₂)_(p)OC(O)NR³—, —(CH₂)_(p)NR³C(O)NR³— (in which the groups R³ are the same or different), —(CH₂)_(p)O—, —(CH₂)_(p)SO₃—, and, optionally in combination with B, a valence bond; p is from 1 to 12; and R³ is hydrogen or a C₁-C₄ alkyl group, and wherein the surface binding monomer has the general formula VII Y¹R¹³  VII wherein Y¹ is selected from the group consisting of

CH₂═C(R¹⁴)CH₂O—, CH₂═C(R¹⁴)CH₂OC(O)—, CH₂═C(R¹⁴)OC(O)—, CH₂═C(R¹⁴)O—, CH₂═C(R¹⁴)CH₂OC(O)N(R¹⁵)—, R¹⁶OOCCR¹⁴═CR¹⁴C(O)O—, R¹⁴CH═CHC(O)O—, R¹⁴CH═C(COOR¹⁶)CH₂C(O)—O—,

wherein: R¹⁴ is hydrogen or a C₁-C₄ alkyl group; R¹⁵ is hydrogen or a C₁-C₄ alkyl group or R¹⁵ is R¹³; R¹⁶ is hydrogen or a C₁₋₄ alkyl group; A¹ is —O— or —NR¹⁵—; and K¹ is selected from the group consisting of —(CH₂)_(q)OC(O)—, —(CH₂)_(q)C(O)O—, —(CH₂)_(q)OC(O)O—, —(CH₂)_(q)NR¹⁷, —(CH₂)_(q)NR¹⁷C(O)—, —(CH₂)_(q)C(O)NR¹⁷—, —(CH₂)_(q)NR¹⁷C(O)O—, —(CH²)_(q)OC(O)NR¹⁷—, —(CH₂)_(q)NR¹⁷C(O)NR¹⁷— (in which the groups R¹⁷ are the same or different), —(CH₂)_(q)O—, —(CH₂)_(q)SO₃—, and a valence bond; q is from 1 to 12; and R¹⁷ is hydrogen or a C₁-C₄ alkyl group; and R¹³ is a surface binding group, selected from hydrophobic groups and cross-linkable groups B²R²⁰; wherein B² is selected from the group consisting of straight or branched alkylene, oxaalkylene and oligo-oxaalkylene chain optionally containing one or more fluorine atoms up to and including perfluorinated chains, and a valence bond; and R²⁰ is a cross-linkable group selected from the group consisting of ethylenically and acetylenically unsaturated groups containing radicals; aldehyde groups; silane and siloxane groups containing one or more substituents selected from halogen atoms and C₁₋₄ alkoxy groups; hydroxyl; amino; carboxyl; epoxy; —CHOHCH₂Hal (in which Hal is selected from chlorine, bromine and iodine atoms); succinimido; tosylate; triflate; imidazole carbonyl amino; optionally substituted triazine groups, acetoxy; mesylate; carbonyl di(cyclo)alkyl carbodiimidoyl; isocyanate, acetoacetoxy; and oximino; and wherein the diluent monomer is a nonionic monomer; b) providing a pharmaceutical solution comprising a pharmaceutically active agent in solution in a solvent, wherein the pharmaceutically active agent has a molecular weight of up to 1200 D and the solvent is capable of swelling the said coating; and c) contacting the coated implant with the pharmaceutical solution at a temperature and for a time to allow swelling of the coating and dispersal of active through the polymer matrix to produce a pharmaceutically active loaded implant.
 53. A process according to claim 52 in which the polymer matrix is substantially non-biodegradable.
 54. A process according to claim 52 wherein providing the sterile coated implant comprises: a1) coating a biostable implant with a coating composition containing the polymer of the matrix, or a precursor thereof, a2) curing the polymer to form the said polymer matrix; and a3) sterilising the implant coated with the polymer matrix.
 55. A process according to claim 52 in which the coating composition contains a cross-linkable polymer and in which curing involves cross-linking the polymer.
 56. A process according to claim 52 in which R¹³ is a straight chain alkyl having 8 to 18 carbon atoms.
 57. A process according to claim 52 in which R²⁰ comprises a silane group containing at least one substituent selected from halogen atoms and C₁₋₄-alkoxy groups.
 58. A process according to claim 52 in which R²⁰ is a trimethoxysilyl group.
 59. A process according to claim 52 in which the thickness of the coating of polymer matrix of the sterile coated implant is in the range 500 nm to 500 μm.
 60. A process according to claim 52 in which both inner and outer surfaces of the stent are coated with polymer matrix and both polymer coated surfaces are contacted with pharmaceutical solution in step c).
 61. A process according to claim 52 in which the ratio of thickness of polymer matrix on the outer to the inner surface is (at least 1.5):1.
 62. A process according to claim 52 in which the pharmaceutically active agent is selected from the group consisting of dipyridamole, angiopeptin, taxol, roxithromycin, rapamycin, tetradecylthioacetic acid, aspirin, etoposide and dexamethasone. 